Plaque Deposition Research Articles

In silico Evaluation and Neuroprotective Effect of Jasmonic Acid on Sleep Deprivation Induced Alzheimer’s in Zebrafish

Background:Disturbances in the sleep cycle have been often associated with the depletion of oxidant enzymes and deposition of beta-amyloid plaques leading to neurodegeneration in Alzheimer's disease (AD). Healthy sleep time and sleep cycles were proven to clear the betaamyloid out of the brain and also promote the synthesis and functions of anti-oxidant enzymes.Objective:Jasmonic acid was evaluated to enhance the cognition and acetylcholine enzyme in the sleep deprivation-induced Alzheimer's by using the zebrafish model.Methods:The molecular properties, bioactivity score, and pharmacokinetic parameters of jasmonic acid were predicted using Molinspiration, SwissADME, and PreADMET tools. Jasmonic acid obeys Lipinski's rule and has significant bioavailability and blood-brain barrier penetration. The prediction of binding energy and interactions of jasmonic acid with six selected receptors was performed using AutoDock 4.2 software. It has significant binding affinity and interactions with different receptors which predict a multi-target potential using in-silico studies. In vivo neurobehavioral analysis of jasmonic acid was performed with zebrafish by using T-maze, Y-maze, and inhibitory avoidance apparatus and the results reveal Jasmonic acid produces more memory retention in zebrafish. In vitro assays of jasmonic acid on acetylcholinesterase enzyme level, glucose level, catalase activity, and lipid peroxidation activity were performed. Jasmonic acid shows cholinesterase inhibition, it acts as a good anti-oxidant and increases glucose metabolism on zebra fish brain homogenate using various assays. Jasmonic acid decreases neurodegeneration, and amyloid deposits in zebrafish brains using histopathological studies.Results:In silico molecular docking studies, in vitro assays, in vivo neurobehavioral analysis and histopathological studies reveal that jasmonic acid showed significant activity against sleep deprivation- induced AD in the zebrafish model.Conclusion:Hence, jasmonic acid will be carried out for further preclinical and clinical studies in order to prove the same for the management of Alzheimer's disease.

Antibody binding of amyloid beta peptide epimers/isomers and ramifications for immunotherapies and drug development

Extracellular deposition of amyloid beta (Aβ) peptide is a contributing factor of Alzheimer’s disease (AD). Considerable effort has been expended to create effective antibodies, or immunotherapies, targeting Aβ peptides. A few immunotherapies are thought to provide some benefit. It is possible that a contributing factor to the responses of such therapies may be the presence of modified, or aberrant, Aβ peptides found in AD patients. These aberrations include the isomerization and epimerization of L-Asp and L-Ser residues to form D-Asp, L/D-isoAsp, and D-Ser residues, respectively. An effective methodology is essential to isolate all Aβ peptides and then to quantify and locate the aberrant amino acids. Modifications to Aβ peptides may elevate the deposition of Aβ plaques and/or contribute to the neurodegeneration in AD patients, and may alter the binding affinity to antibodies. Herein, we used immunoprecipitation to examine the binding affinity of four antibodies against 18 epimeric and/or isomeric Aβ peptides compared to wild type (all L) Aβ peptide. Tandem mass spectrometry was used as a detection method, which also was found to produce highly variable results for epimeric and/or isomeric Aβ.

Case Report: Smoking as the risk factor of persistent STEMI after primary percutaneous coronary intervention: how it could be happen?

Background Acute coronary syndrome (ACS) is a common disease. Smoking may increase the risk of ACS. The most advantageous therapy is percutaneous coronary intervention. This therapy may fail which is no-reflow phenomenon as the result. Total occlusion may increase the risk of no-reflow phenomenon which it could be worse with smoking as the habits. ST-elevation myocardial infarction (STEMI) may show in electrocardiogram (ECG). Case description A 37-year-old male came to the hospital with chest pain as the main complaint. ECG examination showed that there was wide anterior STEMI. Coronary angiography was then done and confirmed that there was total occlusion in left anterior descending artery. After two days hospitalization, the patient developed to cardiogenic shock and lead to acute decompensated heart failure. An ECG showed there was STEMI anterior after primary PCI. Discussion Many chemicals agent contain in cigarette smoking and it may induce the lipid oxidation which leads to plaque deposits. Plaque that deposits in coronary artery may rupture and make thrombus occlusion. This occlusion may partial or total, when there is total occlusion, STEMI was the result. Then, releasing the occlusion is needed for this situation ant PCI may be chosen as the therapy. Patient with wide ischemia may result the no-reflow phenomenon which may lead to heart failure and shock cardiogenic as the complication. Conclusion Smoking may induce ACS which leads to STEMI and may increase the failure of PCI therapy. No-reflow phenomenon is the evidence of miscarriage in therapy which it may increase because of smoking.

Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation.

Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer's disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.

Methods for Evaluating the Effectiveness of Home Oral Hygiene Measures-A Narrative Review of Dental Biofilm Indices.

Dental plaque is a biofilm structured in an extracellular matrix of polymers of host and microbial origin; the microorganisms can coexist in harmony with the host, thus guarantying oral health. Environmental modifications can lead to dysbiosis and onset of oral diseases; in fact, plaque is the etiological agent both of periodontal disease and dental decay. The use of an effective oral hygiene index should be considered as a relevant goal for the clinicians and the researchers, and consequently, numerous plaque indices have been proposed during the years. The present literature review aims primarily to obtain a complete summary of these scores to assess plaque deposits. It is useful because the clinician/researcher will select the right scoring method for the specific situation only if he knows the available options and if he is aware of both their strengths and weaknesses. This review applies a basic classification of plaque indices that distinguishes the ones that use non-quantitative methods from the ones that use quantitative methods. Non-quantitative methods are more subjective because they are based on the ability of the clinician to point out the presence or the entity of deposits, while quantitative methods introduce objectifiable means to measure plaque deposits.

Smilagenin induces expression and epigenetic remodeling of BDNF in alzheimer's disease

BackgroundSmilagenin (SMI) is a lipid-soluble steroidal sapogenin, extracted from traditional Chinses medicinal herbs Radix Asparagi, which is extracted from the dry root of Asparagus cochinchinensis (Lour.) Merr. We previously found that SMI significantly increased brain-derived neurotrophic factor (BDNF) expression in Aβ-intoxicated SH-SY5Y cells. MethodsIn this study, we performed behavioral tests to analyze cognitive function of WT and APP/PS1 mice treated with or without SMI, and found that SMI could significantly improve the learning and memory ability of APP/PS1 mice. Moreover, immunofluorescence and ELISA results showed that SMI pretreatment could effectively reduce the deposition of β-amyloid plaques in the cortex and hippocampus of APP/PS1 mice (26 mg/kg/day for 60 days) and inhibit the secretion of Aβ1-42 in N2a/APPswe cells (10 μM concentration for 24 hours). ResultsMechanistically, SMI enhanced BDNF mRNA expression, elevated the global level of H3AC and H4AC, and increased the expression of P300 in AD models. Furthermore, chromatin immunoprecipitation results showed that SMI could increase the levels of H3AC and H4AC at the promoter of BDNF promoter Ⅱ and Ⅳ, indicating that SMI epigenetically regulates BDNF expression through HAT enhancement. To further verify the critical role of P300 by which SMI upregulated histone acetylation in BDNF, AD mice were treated with SMI and C646 simultaneously. Behavioral experiments showed that the improvement effects of SMI on cognitive impairment were abolished after P300 inhibition in APP/PS1 mice. ConclusionsOur research for the first time demonstrated that SMI showed neuroprotective effects by increasing the expression of P300 protein, thus upregulating histone acetylation levels in the promoter region of BDNF and promoting its transcription. Our findings provide an important theoretical basis for the treatment of Alzheimer's disease with SMI extracted from Asparagus cochinchinensis (Lour.) Merr.

Untangling Alzheimer's disease with spatial multi-omics: a brief review.

Alzheimer's disease (AD) is the most common form of neurological dementia, specified by extracellular β-amyloid plaque deposition, neurofibrillary tangles, and cognitive impairment. AD-associated pathologies like cerebral amyloid angiopathy (CAA) are also affiliated with cognitive impairment and have overlapping molecular drivers, including amyloid buildup. Discerning the complexity of these neurological disorders remains a significant challenge, and the spatiomolecular relationships between pathogenic features of AD and AD-associated pathologies remain poorly understood. This review highlights recent developments in spatial omics, including profiling and molecular imaging methods, and how they are applied to AD. These emerging technologies aim to characterize the relationship between how specific cell types and tissue features are organized in combination with mapping molecular distributions to provide a systems biology view of the tissue microenvironment around these neuropathologies. As spatial omics methods achieve greater resolution and improved molecular coverage, they are enabling deeper characterization of the molecular drivers of AD, leading to new possibilities for the prediction, diagnosis, and mitigation of this debilitating disease.

LPS priming before plaque deposition impedes microglial activation and restrains Aβ pathology in the 5xFAD mouse model of Alzheimer’s disease

Microglia have an innate immunity memory (IIM) with divergent functions in different animal models of neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by chronic neuroinflammation, neurodegeneration, tau tangles and β-amyloid (Aβ) deposition. Systemic inflammation has been implicated in contributing to the progression of AD. Multiple reports have demonstrated unique microglial signatures in AD mouse models and patients. However, the proteomic profiles of microglia modified by IIM have not been well-documented in an AD model. Therefore, in the present study, we investigate whether lipopolysaccharide (LPS)-induced IIM in the pre-clinical stage of AD alters the microglial responses and shapes the neuropathology. We accomplished this by priming 5xFAD and wild-type (WT) mice with an LPS injection at 6 weeks (before the robust development of plaques). 140 days later, we evaluated microglial morphology, activation, the microglial barrier around Aβ, and Aβ deposition in both 5xFAD primed and unprimed mice. Priming induced decreased soma size of microglia and reduced colocalization of PSD95 and Synaptophysin in the retrosplenial cortex. Priming appeared to increase phagocytosis of Aβ, resulting in fewer Thioflavin S+ Aβ fibrils in the dentate gyrus. RIPA-soluble Aβ 40 and 42 were significantly reduced in Primed-5xFAD mice leading to a smaller size of MOAB2+ Aβ plaques in the prefrontal cortex. We also found that Aβ-associated microglia in the Primed-5xFAD mice were less activated and fewer in number. After priming, we also observed improved memory performance in 5xFAD. To further elucidate the molecular mechanism underlying these changes, we performed quantitative proteomic analysis of microglia and bone marrow monocytes. A specific pattern in the microglial proteome was revealed in primed 5xFAD mice. These results suggest that the imprint signatures of primed microglia display a distinctive phenotype and highlight the potential for a beneficial adaption of microglia when intervention occurs in the pre-clinical stage of AD.

Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer's disease mouse model through downregulating BACE1 and Aβ generation.

Alzheimer's disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson's disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg-1·d-1, i.g.) for 3 months. At the end of treatment, retinal function and structure were assessed, cognitive function was evaluated in Morris water maze test. We showed that 4-month-old 5×FAD mice displayed distinct structural and functional deficits in the retinas, which were significantly ameliorated by Sal B treatment. In contrast, untreated, 4-month-old 5×FAD mice did not exhibit cognitive impairment compared to wild-type mice. In SH-SY5Y-APP751 cells, we demonstrated that Sal B (10 μM) significantly decreased BACE1 expression and sorting into the Golgi apparatus, thereby reducing Aβ generation by inhibiting the β-cleavage of APP. Moreover, we found that Sal B effectively attenuated microglial activation and the associated inflammatory cytokine release induced by Aβ plaque deposition in the retinas of 5×FAD mice. Taken together, our results demonstrate that functional impairments in the retina occur before cognitive decline, suggesting that the retina is a valuable reference for early diagnosis of AD. Sal B ameliorates retinal deficits by regulating APP processing and Aβ generation in early AD, which is a potential therapeutic intervention for early AD treatment.

Dauricine alleviates cognitive impairment in Alzheimer's disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathological development of AD. Dauricine (DAU) is a bisbenzylisoquinoline alkaloid isolated from Menispermum dauricum DC., which can prevent the influx of extracellular Ca2+ and inhibit the release of Ca2+ from the endoplasmic reticulum. DAU has a potential for anti-AD. However, it is unclear whether DAU can exert its anti-AD effect in vivo by regulating the Ca2+ related signaling pathways. Here, we investigated the effect and mechanism of DAU on D-galactose and AlCl3 combined-induced AD mice based on the Ca2+/CaM pathway. The results showed that DAU (1 mg/kg and 10 mg/kg for 30 days) treatment attenuated learning and memory deficits and improved the nesting ability of AD mice. The HE staining assay showed that DAU could inhibit the histopathological alterations and attenuate neuronal damage in the hippocampus and cortex of AD mice. Studies on the mechanism indicated that DAU decreased the phosphorylation of CaMKII and Tau and reduced the formation of NFTs in the hippocampus and cortex. DAU treatment also reduced the abnormally high expression of APP, BACE1, and Aβ1–42, which inhibited the deposition of Aβ plaques. Moreover, DAU could decrease Ca2+ levels and inhibit elevated CaM protein expression in the hippocampus and cortex of AD mice. The molecular docking results showed that DAU may have a high affinity with CaM or BACE1. DAU has a beneficial impact on pathological changes in AD mice induced by D-galactose and AlCl3 and may act by negative regulation of the Ca2+/CaM pathway and its downstream molecules such as CaMKII and BACE1.

Bayesian regularization networks for micropolar ternary hybrid nanofluid flow of blood with homogeneous and heterogeneous reactions: Entropy generation optimization

This study aims to analyze a Bayesian regularization backpropagation algorithm for micropolar ternary hybrid nanofluid flow over curved surfaces with homogeneous and heterogeneous reactions, Joule heating and viscous dissipation. The ternary hybrid nanofluid consists of nanoparticles of titanium oxide (TiO2), copper oxide (CuO), and silicon oxide (SiO2), with blood as the base fluid. The governing partial differential equations for the fluid flow are converted into ordinary differential equations using a group of self-similar transformations. The ordinary differential equations are solved using an appropriate shooting algorithm in MATLAB. The effects of physical parameters including curvature, micro-polar, radiation, magnetic, Prandtl, Eckert, Schmidt, and homogeneous and heterogeneous chemical reaction parameters are analyzed for velocity, micro rotational, temperature, and concentration profile. Physical quantities of engineering interest like heat transfer rate, mass transfer rate, skin friction coefficient, couple stress coefficient, and entropy generation are also discussed in this study. A Bayesian regularization backpropagation algorithm is also designed for the solution of the ordinary differential equations. The obtained network is analyzed using training state, performance, error histograms, model response, Error autocorrelation, and input-error correlation plots. It is observed that the entropy generation and the Bejan number increase for enhancing Brinkman and radiation parameter. Clinical researchers and biologists may use the results of this computational study to forecast endothelial cell damage and plaque deposition in curved arteries, by which the severity of these conditions can be reduced.

Optimizing energy generation in power-law nanofluid flow through curved arteries with gold nanoparticles

The investigation of blood flow into curved arteries is fascinating and essential to prevent the advancement of vascular disease. Motivated by electro-kinetic manipulation, gold nanoparticles, and their size applications, a mathematical model is developed to explain blood flow, entropy generation, and electro-kinetic energy conversion (EKEC) efficiency in curved arterial flow. To make this study more realistic, a patient-specific overlapped stenosis condition and non-Newtonian (power-law fluid) blood flow model have been considered. The effects of a magnetic field, external heating, and chemical reactions are also included. The Stone’s strongly implicit scheme has been considered to solve the system of non-linear partial differential equations (PDE’s) in the” MATLAB” software. In this numerical investigation, an error tolerance of 10 − 6 has been considered for every iteration step under Stone’s scheme. The significance of various physical parameters, such as nanoparticle volume fraction (m), their size (dp), magnetic field intensity (M), inverse Debye length ( κ ¯ ), flow behavior index (Sc), heat source (H), and chemical reaction parameter (ξ) on the blood flow velocity, temperature, concentration, EKEC efficiency, and entropy generation have been explained graphically. This study also developed stream function contours to describe flow trapping patterns. The findings of this study conclude that the blood flow EKEC efficiency reduces with the presence of nanoparticles and stenosis in the artery. In addition, both flow velocity and entropy enhance by adopting large-size nanoparticles instead of small diametric nanoparticles. Clinical researchers and biologists may use the results of this computational study to forecast endothelial cell damage and plaque deposition in curved arteries with WSS profiles, by which the severity of these conditions can be reduced.

Natural antioxidants that act against Alzheimer's disease through modulation of the NRF2 pathway: a focus on their molecular mechanisms of action.

Characterized by a complex pathophysiology that includes the intraneuronal formation of neurofibrillary tangles and the extracellular deposition of β-amyloid plaques, Alzheimer's disease (AD) is a terminal neurodegenerative disease that causes dementia in older adults. Oxidative stress in the brain is considered as one of the contributing factors to the pathogenesis of AD, and thus, antioxidants have attracted much interest as potential therapeutic agents against the disorder. Natural antioxidants are typically characterized by low acute and chronic toxicity, which facilitates their potential therapeutic application. One important molecular target for the beneficial effects of natural antioxidants is the nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/NRF2). NRF2 is a key transcription factor that orchestrates the cellular antioxidant response through regulating the expression of oxidative stress-related genes harboring the antioxidant response element (ARE) in their promoters. Indeed, in the case of excessive oxidative damage, NRF2 migrates to the nucleus and binds to ARE, activating the transcription of antioxidant protector genes. There is increasing evidence that NRF2 is implicated in AD pathology through dysfunction and altered localization, which renders it as a potential therapeutic target for AD. Thus, this review summarizes the most recent (2018-2023) advances on the NRF2-modulating activity of natural antioxidants observed in vitro and in AD animal models. This information will help elucidate the molecular mechanisms governing the antioxidant activity of such phytochemicals to highlight their therapeutic potential against common neurodegenerative diseases, such as AD.

Fluid-structure interaction study of hemodynamics and its biomechanical influence on carotid artery atherosclerotic plaque deposits

Atherosclerotic plaque deposits are common causes of blood flow disruption in the carotid artery bifurcation and the associated fluid mechanics has been extensively studied using Computational Fluid Dynamics (CFD) and Fluid Structure Interaction (FSI). However, the elastic responses of plaques to hemodynamics in the carotid artery bifurcation has not been deeply studied using either of the above-mentioned numerical techniques. In this study, a two-way FSI study was coupled with CFD technique, using Arbitrary-Lagrangian-Eulerian method, to study the biomechanics of blood flow on nonlinear and hyperelastic calcified plaque deposits in a realistic geometry of the carotid sinus. FSI parameters such as total mesh displacement and von Misses stress on the plaque, as well as flow velocity and blood pressure around the plaques, were analyzed and compared to variables such as velocity streamline, pressure and wall shear stress obtained from CFD simulation in a healthy model. The blood flow simulations reveal complete reversed blood flow behavior in the internal carotid artery, ICAs and external carotid artery, ECAs for both cases. In particular, this study suggests that plaques, irrespective of the masses, possess a high yielding response to hemodynamic forces at the attaching edges, while the surfaces are vulnerable to rupture.

EVs-mediated delivery of CB2 receptor agonist for Alzheimer's disease therapy

Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the unclear mechanism. We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241 (EVs-AM1241) to protect against neurodegenerative progression and neuronal function in AD model mice. According to the results, EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241. The Morris water maze (MWM) and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved. In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning. Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloid β (Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241. Moreover, EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton, indicating that they enhanced neuronal regeneration. RNA sequencing revealed that EVs-AM1241 facilitated Aβ phagocytosis, promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway. Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in model mice, indicating that they are very promising particles for treating AD.

APP/PS1 Gene-Environmental Cadmium Interaction Aggravates the Progression of Alzheimer's Disease in Mice via the Blood-Brain Barrier, Amyloid-β, and Inflammation.

There is limited information about gene-environment interaction on the occurrence and the progression of Alzheimer's disease. To explore the effect of environmental low-dose cadmium (Cd) exposure on the progress of Alzheimer's disease and the underlining mechanism. We administered 1 mg/L, 10 mg/L cadmium chloride (treated groups), and water (control group) to C57BL/6J and APP/PS1 mice through drinking water, from one week before mating, until the offspring were sacrificed at 6 months of age. The behaviors, Cd level, blood-brain barrier (BBB) leakage, Aβ1-42 deposition, and inflammation expression were evaluated in these mice. Mice of both genotypes had similar blood Cd levels after exposure to the same dose of Cd. The toxic effects of Cd on the two genotypes differed little in terms of neuronal histomorphology and BBB permeability. Cd caused a series of pathological morphological changes in the mouse brains and more fluorescent dye leakage at higher doses. Furthermore, the APP/PS1 mice had more severe damage than the C57BL/6J mice, based on the following five criteria. They were increasing anxiety-like behavior and chaos movement, spatial reference memory damage, Aβ plaque deposition in mouse brains, increasing microglia expression in the brain, and IL-6 higher expression in the cortex and in the serum. Low-dose Cd exposure for 6 months increases Aβ plaque deposition and BBB permeability, exacerbates inflammatory responses, and activates microglia, in APP/PS1 mice. APP/PS1 gene-environmental Cd interaction aggravates the progression of Alzheimer's disease in mice.

The effects of low-dose radiation therapy in patients with mild-to-moderate Alzheimer's dementia: an interim analysis of a pilot study.

We aimed to determine whether low-dose radiotherapy (LDRT) is effective in patients with Alzheimer disease (AD). We included patients according to the following criteria: probable Alzheimer's dementia according to the New Diagnostic Criteria for Alzheimer's Disease; confirmation of amyloid plaque deposits on baseline amyloid positron emission tomography (PET); a Korean Mini-Mental State Examination 2nd edition (K-MMSE-2) score of 13-26; and a Global Clinical Dementia Rating (CDR) score of 0.5-2 points. LDRT was performed six times at 0.5 Gy each. Post-treatment cognitive function tests and PET-CT examinations were performed to evaluate efficacy. The medication for AD treatment was maintained throughout the study period. At 6 months after LDRT, neurological improvement was seen in 20% of patients. Patient #2 showed improvement in all domains of the Seoul Neuropsychological Screening Battery II (SNSB-II). Moreover, the K-MMSE-2 and Geriatric Depression Score-Short Form scores improved from 20 to 23 and from 8 to 2, respectively. For patient #3, the CDR score (sum of box score) improved from 1 (4.0) to 1 (3.5) at 3 months follow-up. Moreover, the Z scores for language and related functions, memory, and frontal executive function improved to -2.56, -1.86, and -1.32, respectively at the 6-month follow-up. Two patients complained of mild nausea and mild hair loss during LDRT, which improved after treatment. One of the five patients with AD treated with LDRT experienced a temporary improvement in SNSB-II. LDRT is tolerable in patients with AD. We are currently under follow-up and will conduct cognitive function tests after 12 months after LDRT. A large-scale randomized controlled trial with a longer follow-up period is warranted to determine the effect of LDRT on patients with AD.

Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach

Abstract Alzheimer’s disease (AD) is a multifactorial neurodegenerative central system disease with a high prevalence among the elderly and is the most common form of dementia. Oxidative stress is crucial on AD pathogenesis and leads to deposition of neurofibrillary tangles and Aβ plaques; therefore, the use of natural antioxidants or ROS scavengers could help avoid the formation of these aggregates. Similarly, Aβ-degrading/anti-aggregating molecules could help arrest AD progression. Otherwise, traditional anti-Alzheimer drugs such as acetylcholinesterase inhibitors help improve memory and attention deficits. Nevertheless, all these drugs are extensively metabolized, have low plasma concentration, and cannot cross the blood–brain barrier freely. This review discusses different strategies for nanocarrier conjugation of these drugs for brain targeting and delivery, and new approaches on AD treatment according to the most accepted hypotheses of AD pathogenesis. Although none of the existent compounds or drugs can completely arrest the disease’s progression, nanocarrier development of anti-Alzheimer drugs could help delaying the initial or late stages of neurodegeneration. The discovery of new and more complex nanosystems with multiple approaches in AD treatment is needed and will be the next step in AD treatment in the near future.

Differential expression of SLC30A10 and RAGE in mouse pups by early life lead exposure

BackgroundSLC30A10 and RAGE are widely recognized as pivotal regulators of Aβ plaque transport and accumulation. Prior investigations have established a link between early lead exposure and cerebral harm in offspring, attributable to Aβ buildup and amyloid plaque deposition. However, the impact of lead on the protein expression of SLC30A10 and RAGE has yet to be elucidated. This study seeks to confirm the influence of maternal lead exposure during pregnancy, specifically through lead-containing drinking water, on the protein expression of SLC30A10 and RAGE in mice offspring. Furthermore, this research aims to provide further evidence of lead-induced neurotoxicity. MethodsFour cohorts of mice were subjected to lead exposure at concentrations of 0 mM, 0.25 mM, 0.5 mM, and 1 mM over a period of 42 uninterrupted days, spanning from pregnancy to the weaning phase. On postnatal day 21, the offspring mice underwent assessments. The levels of lead in the blood, hippocampus, and cerebral cortex were scrutinized, while the mice's cognitive abilities pertaining to learning and memory were probed through the utilization of the Morris water maze. Furthermore, Western blotting and immunofluorescence techniques were employed to analyze the expression levels of SLC30A10 and RAGE in the hippocampus and cerebral cortex. ResultsThe findings revealed a significant elevation in lead concentration within the brains and bloodstreams of mice, mirroring the increased lead exposure experienced by their mothers during the designated period (P < 0.05). Notably, in the Morris water maze assessment, the lead-exposed group exhibited noticeably diminished spatial memory compared to the control group (P < 0.05). Both immunofluorescence and Western blot analyses effectively demonstrated the concomitant impact of varying lead exposure levels on the hippocampal and cerebral cortex regions of the offspring. The expression levels of SLC30A10 displayed a negative correlation with lead doses (P < 0.05). Surprisingly, under identical circumstances, the expression of RAGE in the hippocampus and cortex of the offspring exhibited a positive correlation with lead doses (P < 0.05). ConclusionSLC30A10 potentially exerts distinct influence on exacerbated Aβ accumulation and transportation in contrast to RAGE. Disparities in brain expression of RAGE and SLC30A10 may contribute to the neurotoxic effects induced by lead.

Particle Filter Based Framework for the Prognosis of Atherosclerosis via Lumped Cardiovascular Modeling

Atherosclerosis refers to the plaque deposition in the arteries that can eventually lead to any of the three cardiovascular diseases, namely, heart attack, stroke, or peripheral vascular disease, depending upon the site of the blockage in the human arterial network. This work attempts to prognose this pathological condition via lumped cardiovascular modeling while utilizing the radial artery blood pressure measurements. To achieve this, the cardiovascular system has been modeled as a third order non-linear system with explicit emphasis on the systemic circulation. The parameters of the model are estimated using non-linear least squares estimation technique by minimizing the error between the measured and the estimated arterial pressure waveforms. The arterial pressure is found to be sensitive to three of the model parameters, namely, arterial compliance, systemic vascular resistance, and the peak cardiac muscle elastance. Based on the analysis, a growth model of systolic blood pressure is developed as a function of the arterial blockage. A particle filter based mathematical framework is then utilized to predict the time it would take to reach the stage of critical arterial blockage that may cause heart attacks.