Treatment Of AD Research Articles

Progress in mitochondrial and omics studies in Alzheimer's disease research: from molecular mechanisms to therapeutic interventions.

Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and β-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.

Rhei Undulati Rhizoma attenuates memory decline and reduces amyloid-β induced neuritic dystrophy in 5xFAD mouse

BackgroundAlzheimer's disease (AD) is a common type of dementia characterized by amyloid-β (Aβ) accumulation, lysosomal dysfunction, and tau hyperphosphorylation, leading to neurite dystrophy and memory loss. This study aimed to investigate whether Rhei Undulati Rhizoma (RUR), which has been reported to have anti-neuroinflammatory effect, attenuates Aβ-induced memory impairment, neuritic dystrophy, and tau hyperphosphorylation, and to reveal its mode of action.MethodsFive-month-old 5xFAD mice received RUR (50 mg/kg) orally for 2 months. The Y-maze test was used to assess working memory. After behavioral testing, brain tissue was analyzed using thioflavin S staining, western blotting, and immunofluorescence staining to investigate the mode of action of RUR. To confirm whether RUR directly reduces Aβ aggregation, a thioflavin T assay and dot blot were performed after incubating Aβ with RUR.ResultsRUR administration attenuated the Aβ-induced memory impairment in 5xFAD mice. Furthermore, decreased accumulation of Aβ was observed in the hippocampus of the RUR-treated 5xFAD group compare to the vehicle-treated 5xFAD group. Moreover, RUR reduced the dystrophic neurites (DNs) that accumulate impaired endolysosomal organelles around Aβ. In particular, RUR treatment downregulated the expression of β-site amyloid precursor protein cleaving enzyme 1 and the hyperphosphorylation of tau within DNs. Additionally, RUR directly suppressed the aggregation of Aβ, and eliminated Aβ oligomers in vitro.ConclusionsThis study showed that RUR could attenuate Aβ-induced pathology and directly regulate the aggregation of Aβ. These results suggest that RUR could be an efficient material for AD treatment through Aβ regulation.Graphical

From Lab Bench to Hope: Emerging Gene Therapies in Clinical Trials for Alzheimer's Disease.

Alzheimer's disease is a progressive neurodegenerative disorder that affects memory and cognitive abilities, affecting millions of people around the world. Current treatments focus on the management of symptoms, as no effective therapy has been approved to modify the underlying disease process. Gene therapy is a promising approach that can offer disease-modifying treatment for AD, targeting various aspects of the pathophysiology of the disease. This review presents a comprehensive overview of the current state of gene therapy research for AD, with a specific focus on clinical trials and preclinical studies that have used nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), apolipoprotein E2 (APOE2), and human telomerase reverse transcriptase (hTERT) as therapeutic gene therapy approaches. These gene targets have shown potential to alleviate the neuropathology of AD in animal studies and have demonstrated feasibility and safety in non-human primates. Despite the failure of the NGF gene therapy approach in clinical trials, we have reviewed and highlighted the reported findings and evaluations from the trials. Furthermore, the review included the conclusions of postmortem brain tissue analysis of AD patients who received NGF gene therapy. The goal is to learn from the failed trials and improve the approach in the future. Although gene therapy shows promise, it faces several challenges and limitations, including optimizing gene delivery methods, enhancing safety and efficacy profiles, and determining long-term results. This review contributes to the growing body of literature on innovative treatments for AD and highlights the need for more research and development to advance gene therapy as a viable treatment option for AD.

Targeting mitochondrial dysfunction in atopic dermatitis with trilinolein: A triacylglycerol from the medicinal plant Cannabis fructus

BackgroundAtopic dermatitis (AD) is a common skin condition that causes chronic and recurring eczema lesions. Prior research has indicated that Cannabis fructus, the mature fruit of Cannabis sativa, has an antioxidant effect. Historically, Cannabis fructus has been used in cosmetics and medicine. However, there is limited knowledge regarding its biological components and the mechanisms by which it prevents and treats AD. ObjectivesHPLC-ESI-MS/MS analysis was utilized to identify the main compounds of Cannabis fructus, and trilinolein was extracted using chromatographic techniques. The potential of trilinolein in the prevention of AD was assessed, and its underlying mechanisms of action were elucidated. MethodsThe distribution of distinct cellular subpopulations and the principal biological processes implicated in the pathogenesis of AD were assessed through a comparative study involving chronic AD patients and healthy controls (HCs). Differential gene expression was validated in clinical samples from the lesions of AD patients and the healthy skin of controls. The pharmacodynamic activity of trilinolein was validated in dinitrochlorobenzene (DNCB)-induced BALB/c mice and in IL-4- and TNF-α-induced HaCaT cells. Proteomics analyse was employed to investigate its mechanisms. ResultsSingle-cell transcriptome analysis revealed that chronic AD is characterized by abnormal keratinocyte differentiation and oxidative stress damage. When topically applied, trilinolein can effectively improve AD-like skin lesions induced by DNCB. It increases the expression of terminal differentiation proteins and decreases the expression of NADPH oxidase 2 (NOX2), with a therapeutic effect comparable to that of the positive control drug crisaborole. Additionally, trilinolein reduced ROS fluorescence intensity, restored mitochondrial morphology and membrane potential, and decreased mitochondrial DNA (mtDNA) release in keratinocytes stimulated with IL-4 and TNF-α. Moreover, trilinolein increased the protein expression of AhR, CYP1A1, and Nrf2 in a dose-dependent manner. The effect of trilinolein on keratinocyte terminal differentiation proteins and ROS levels was blocked by the addition of an AhR inhibitor. ConclusionThe study suggests that trilinolein from Cannabis fructus alleviates NOX2-dependent mitochondrial dysfunction and repair the skin barrier via AhR-Nrf2 pathway, making it a promising agent for the prevention and treatment of AD.

Dysregulated expression of miR-140 and miR-122 compromised microglial chemotaxis and led to reduced restriction of AD pathology

BackgroundDeposition of amyloid β, which is produced by amyloidogenic cleavage of APP by β- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc.MethodsThe global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology.ResultsIn this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aβ were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aβ phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets.ConclusionsOur results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.

The Use of Nano-based Drug Delivery Systems for Neurodegenerative Disorders

ABSTRACT Blood–brain interfaces surrounding the central nervous system (CNS) present problems for targeted drug delivery, which limits the bioavailability of therapies for the diagnosis and treatment of neurological illnesses such as Alzheimer’s diseases and Parkinson’s diseases (AD/PD). Over the past 10 years, research has concentrated on creating novel approaches to get around these restrictions and effectively transport medications to the CNS. The protective barriers surrounding the CNS can be penetrated by nanoparticles (NPs), which have the ability to encapsulate medicines with prolonged drug release patterns and customizable physiochemical properties. To find out more about drug delivery systems, blood–brain barrier, NPs, neurodegenerative illnesses, AD and PD, and their treatment applications, a ScienceDirect, PubMed, and Google Scholar search was done. After analysis using the keywords/phrases, relevant articles were determined to be completed. Because nanotechnology is a potent substitute for traditional drug delivery systems, it thus offers new hope for the treatment of AD and PD for example. The possible use of techniques based on NPs in neurodegenerative disorders and their therapeutic implications are covered briefly in this work.

Is TEVAR an Effective Approach to Prevent Complications after Surgery for Aortic Dissection Type A? A Systematic Review.

Introduction: A residual false lumen after treatment for Aortic Dissection type A (AD) has been associated with early complications, such as A malperfusion or rupture and mid-term or delayed complications, such as aneurysm formation or dissection expansion. Thoracic Endovascular Aortic Repair (TEVAR) is considered an effective solution by several surgical teams to prevent future complications. In this systematic review, all published data regarding the implementation of TEVAR after previous treatment for AD were collected in order to investigate indications, methods, clinical outcomes and aortic remodeling in these patients. Methods: The aim of this study was to investigate the indications, the methods and the efficacy of TEVAR usage after surgical treatment of AD. Data for this study were collected from four widely used medical databases (MEDLINE, SCIENCE DIRECT, GOOGLE SCHOLAR, OVID). All the results for each database were recorded and were analyzed with a systematic method. Techniques and clinical outcomes were investigated. Aortic remodeling was evaluated based on the following parameters in these studies: aortic diameter, true lumen diameter, false lumen diameter, false lumen thrombosis and false lumen patency. Results: The results obtained from the search among all databases comprised 1410 articles and of these articles 9 were included in the review. The majority of the studies were retrospective (seven out of nine studies), while no study was randomized. The total number of patients was 157 and 133 of them (84.7% of patients) were treated with TEVAR in zone 3 without extension below the diaphragm intraoperatively. Among 142 patients, the calculated mortality rate was 12.7% (18 of 142 patients), with 2.8% (4 of 142 patients) presenting with stroke. The percentage of patients with total or partial thrombosis combined was 65.9% (62 patients in a population of 92). The reintervention rate was 18.7%. Conclusions: TEVAR after AD surgery is an approach usually chosen in clinical practice, but the criteria of its usage are uncertain. This method is safe and enhances aortic remodeling with an acceptable reintervention rate. Definite guidelines in this field should be created in order to delineate whether TEVAR after AD surgery is beneficial as a preventive measure to aorta-related complications and to decide under which criteria this approach should be chosen.

Development of novel fluoro-substituted rivastigmine derivatives as selective AChE inhibitors for the treatment of AD

Development of novel fluoro-substituted rivastigmine derivatives as selective AChE inhibitors for the treatment of AD

Zexieyin formula alleviates Alzheimer's disease via post-synaptic CaMKII modulating AMPA receptor: Involved in promoting neurogenesis to strengthen synaptic plasticity in mice hippocampus

BackgroundAlzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD. PurposeThe study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action. MethodsWe used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD. ResultsThe results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells. ConclusionZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.

Exploring Dimethylsulfoniopropionate as a potential treatment for Alzheimer's disease: A study using the 3 × Tg-AD mouse model

BackgroundAlzheimer's disease (AD), the most common neurodegenerative disorder, affects a broad spectrum of aging populations. AD is characterized by pathological amyloid-β (Aβ) plaques and neurofibrillary tangles, leading to neural degeneration and cognitive decline. The lack of effective treatments for AD highlights the urgent need for novel therapeutic agents, particularly in the early stages. Dimethylsulfoniopropionate (DMSP) is a natural marine compound with antioxidant and neuroprotective properties. However, studies on the efficacy of DMSP in the treatment of AD and its associated mechanisms are limited. PurposeThis study aimed to explore the therapeutic effects and mechanisms of action of DMSP as an AD treatment using a preclinical 3 × Tg-AD mouse model. MethodsThe research involved administering DMSP (7 μg/mL and 11 μg/mL in drinking water) to four-month-old 3 × Tg-AD mice consecutively for three months. The Y-maze test, novel object recognition test, and Morris water maze test were used to assess memory and learning ability. The relative expression levels and distribution of proteins relevant to Aβ and tau pathology, synapses, and glial cells were analyzed using western blotting and immunofluorescence assays. Additionally, proteomic and bioinformatics approaches were used to explore the potential targets of DMSP treatment. ResultsDMSP-treated AD mice showed significantly enhanced cognitive function, suggesting that DMSP mitigates memory and learning impairments in AD. Moreover, DMSP diminished the abnormal accumulation of Aβ and phosphorylated tau in both the cortex and hippocampus, which are crucial hallmarks of AD pathology. In addition to its neuroprotective properties, DMSP restored synaptic density and the expression of synaptic and neuronal proteins, which are essential for proper brain function. DMSP displayed anti-inflammatory properties, as evidenced by its ability to suppress inflammatory astrocytes and maintain microglial homeostasis. Notably, DMSP facilitated the maturation of oligodendrocytes (OLs) from oligodendrocyte progenitor cells (OPCs), a critical process in the development of the brain myelination architecture. Proteomic analysis revealed that DMSP positively influenced biological processes crucial for oligodendrocyte development, myelination, and axonal ensheathment, which are often compromised in patients with AD. Protein validation and brain tissue staining supported the role of DMSP in preserving myelin enrichment and sheath integrity. These therapeutic effects were largely attributed to the enhanced expression of myelin-associated glycoprotein (Mag) and tetraspanin Cd9. ConclusionOverall, our findings highlight DMSP as a promising novel therapeutic candidate for AD, offering multifaceted benefits in cognitive and memory enhancement, reduction of Aβ and tau pathology, neuronal synapse protection, anti-inflammatory effects, and myelin sheath restoration as an innovative target compared to other studies. In addition to being a potentially effective treatment for AD, DMSP may also have the potential to address other neurodegenerative diseases that are closely associated with myelin impairment.

Aβ42 and ROS dual-targeted multifunctional nanocomposite for combination therapy of Alzheimer’s disease

Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aβ aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer’s disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aβ42, we developed an Aβ42 and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aβ-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aβ42 misfolding, accelerating Aβ42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aβ clearance exhibited by this Aβ42 and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.

Limbic-predominant age-related TDP-43 encephalopathy: Amnestic-predominant cognitive decline beyond Alzheimer’s disease

Alzheimer’s disease (AD) is the main cause of neurodegenerative cognitive impairment leading to dementia. It is characterized by progressively worsening cognitive impairment with a predominant amnestic involvement. However, it is not the sole neurodegenerative disease presenting such symptoms, particularly prevalent among the elderly in our society. Recently, limbic-predominant age-related TDP-43 encephalopathy (LATE) has been identified. The diagnosis of LATE in living individuals is very complex due to the lack of universally applicable diagnostic criteria and reliable biomarkers. Nonetheless, its relevance is not diminished, as up to 20% of cases diagnosed with AD, especially in individuals over 80 years old, are actually due to LATE, and over 50% of AD cases have associated LATE copathology. This narrative review aims to address several aspects related to LATE, including identifying its typical clinical features, gaining a better understanding of its pathogenesis in pure cases and those associated with other neurodegenerative diseases, advancements in diagnostic tools for detecting LATE during life, its anatomopathological definition and staging, and potential advances in treatment. In the current era of potentially disease-modifying anti-amyloid treatments for AD, understanding both pure LATE and its co-pathology with AD is of particular relevance.

Hypoglycemic TCM formulas (Huangqi-Gegen drug pair) have the potential as an Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a neurological disorder. There is a considerable unmet medical need among those suffering from it. Hypothesis and purposeGiven the link between type-2 diabetes mellitus (T2DM) and AD, hypoglycemic traditional Chinese medicine formulas (TCMFs) may be a treatment for AD. We investigated the possibility of identifying anti-AD medicines in hypoglycemic TCMFs and presented another option for the screening of AD medications. Study design and methodsParalysis of the transgenic Caenorhabditis elegans (C. elegans) strain CL4176 (caused by amyloid beta (Aβ)1–42 aggregates) was used to evaluate the anti-AD effect. The toxicity and neurodegeneration induced by neuronal expression of Aβ in the transgenic C. elegans strain CL2355 were determined using a 5-hydroxytryptamine (5-HT) assay. The transgenic Aβ-expressing strain CL 2006 and transgenic tau-expressing strain BR5270 were used to explore the effect of TCMFs on protein expression in C. elegans using ELISAs. Then, network pharmacology was used to determine the mechanism of action. The Traditional Chinese Medicine Inheritance Support System platform was used to investigate prescription patterns, core drugs, and optimum combinations of hypoglycemic TCMFs for AD. ResultsSixteen hypoglycemic TCMFs prolonged the PT50 (half paralysis time) of the CL4176 strain of C. elegans, reduced the percentage of worms paralyzed. The results of network pharmacology showed that prostaglandin-endoperoxide synthase 2 (PTGS2) and acetylcholine esterase (AChE) are main targets of hypoglycemic TCMFs. Enriched pathway analysis showed that the cholinergic receptor-related pathway was the core pathway of hypoglycemic TCMFs. According to the “four qi and five flavors” system of TCM theory, the main pharmacological qualities were “cold” and “sweet.” Through the analysis by TCMISS, we found that Huangqi-Gegen drug pair as the significant Chinese herbs of hypoglycemic TCMFs. The Huangqi–Gegen pairing had the most robust therapeutic effect when delivered at a 2:1 (v/v) ratio. It reduced the paralysis caused by 5-HT, decreased protein expression of AChE and PTGS2, and reduced Aβ deposition in the brain of the CL2006 strain of C. elegans. ConclusionsHuangqi–Gegen is a promising treatment of AD, and its mechanism may be induced by suppressing the protein production of AChE and PTGS2, reducing 5-HT intake, and then decreasing Aβ deposition.

Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease

BackgroundAlzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aβ)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aβ protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo.MethodsClarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally.ResultsOverall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3–6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%).ConclusionsLecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care.Trial registrationClinicalTrials.gov numbers: Clarity AD NCT03887455)

Sercocephalous latifolius fruit attenuates aluminum chloride-induced oxidative stress and neurotoxicity in Drosophila melanogaster via Drn1 regulation of the IMD signaling pathway

IntroductionAlzheimer disease (AD) is a form of dementia that is a heterogeneous dysfunction of various pathophysiological features. Its morphological characteristics consist of tau aggregates and amyloid plaques. The need for novel therapy in the treatment of AD is required. Hence use of antioxidant, natural products are widely employed for the management and treatment of AD and other neurodegenerative diseases. However, there are still a lot of limitations. Sercocephalous latifolius fruit (SLF) is also known as the African peach and has numerous well-being-endorsing advantages. The Chinese name of SLF is Feizhou hong tao, while the Nigeria (Yoruba) name is Eso Gberesi. It can be grown all over the world. SLF has anti-neurodegenerative properties, however, there is a lack of evidence on their probable molecular mechanism for novel therapeutic properties. Investigations have been conducted on the SFL which shows its medicinal capability, but its ability to attenuate neurodegenerative diseases such as AD is yet to be fully elucidated, and the molecular signally pathways whichmay serve as a therapeutic target. MethodsThe modulatory effect of SLF on aluminum chloride-induced neurotoxicity and oxidative stress in Drosophila melanogaster via Defense repressor-1 (Drn1) regulation of immune deficiency (Imd) signaling pathway which may be a useful therapeutic target. D. melanogaster was divided into nine groups. Group 1 served as the basal control as they were fed with a normal basal diet, group 2 served as the negative control as they were fed with Basal Diet and 0.5 ml of aluminum/100 ml distilled water, group 3 served as the positive control as they were fed with basal diet 0.5 ml aluminum chloride/100 ml distilled water and Garlic acid, group 4 and 5 were fed with basal diet and 0.1 and 1 % SLF respectively, group 6 and 7 were fed with basal diet, aluminum chloride and 0.1 and 1.0 % respectively, group 8 and 9 were fed with basal diet, garlic acid, aluminum chloride and 0.1 and 1.0 % SLF respectively. All the groups were left for seven days. The experiment was conducted for 3 months, and the fruit flies were changed every 5 days. ResultsSuperoxide dismutase, catalase, malondialdehyde, and nitric oxide enzymatic enzymes were assayed. However, the relative expression of Defense repressor-1 was also determined both in vitro and on aluminum-induced neurodegenerative D. melanogaster tissue. A significant increase was observed in the catalase when 0.1 % and 1 % were compared, it could be inferred that the extract proved effective at low concentrations, since its highest antioxidant potential was observed at low concentrations. The results revealed decrease in the activity of malondialdehyde, superoxide dismutase, and nitric oxide biological enzymes in the test groups. There was upregulation of Defense repressor -1 in groups 3, 4, 5, and 6, when compared with the positive and negative control, respectively. DiscussionThe result provides evidence that SLF has the potential of upregulating defense repressor genes and modulating biological antioxidant enzymes, which could be further exploited to fully understand the underlying molecular mechanisms responsible for the attenuation of neurotoxicity, oxidative stress, and neurodegenerative diseases such as AD. The results suggest that SLF may be useful as a therapeutic target in AD and other neurodegenerative diseases

Innovative approaches and challenges in antibody-based therapeutics for Alzheimer’s disease

Neurological conditions, such as Alzheimer’s disease (AD) and tau-related pathologies, represent a substantial worldwide health dilemma. This review explores recent advancements and challenges in single-domain antibody (VHH)-based strategies targeting beta-secretase 1 (BACE1) inhibition and tau-related therapeutics. The methodology adopted in this study involved a comprehensive search of databases (e.g., Scopus, PubMed, and Google Scholar), with recent articles cited to provide an up-to-date overview. The research examines the limitations of current AD treatments, emphasizing the need for innovative techniques. We, further, discuss potential gene transfer methods using adeno-associated virus-based vectors for central nervous system delivery of single-domain immunoglobins/antibodies (VHHs) to inhibit BACE1. In addition, insights into anti-tau therapeutics, including passive immunization and active vaccines, offer novel insights into research. These findings hold implications for the redesign of therapies for neurodegenerative disorders and the advancement of clinical understanding.

Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer’s disease by inhibiting neuroinflammation and neuronal necroptosis

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.ResultsWe examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.ConclusionsOur findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.

A new vision of the efficacy of both CAR-NK and CAR-T cells in treating cancers and autoimmune diseases.

Chimeric Antigen Receptor (CAR) based therapies are becoming increasingly important in treating patients. CAR-T cells have been shown to be highly effective in the treatment of hematological malignancies. However, harmful therapeutic barriers have been identified, such as the potential for graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome (CRS). As a result, CAR NK-cell therapy is expected to be a new therapeutic option. NK cells act as cytotoxic lymphocytes, supporting the innate immune response against autoimmune diseases and cancer cells by precisely detecting and eliminating malignant cells. Genetic modification of these cells provides a dual approach to the treatment of AD and cancer. It can be used through both CAR-independent and CAR-dependent mechanisms. The use of CAR-based cell therapies has been successful in treating cancer patients, leading to further investigation of this innovative treatment for alternative diseases, including AD. The complementary roles of CAR T and CAR NK cells have stimulated exploration in this area. Our study examines the latest research on the therapeutic effectiveness of these cells in treating both cancer and ADs.

ZOZI-Seg: A transformer and UNet cascade network with Zoom-Out and Zoom-In scheme for aortic dissection segmentation in enhanced CT images

Background & objectiveAortic dissection (AD) is a serious condition requiring rapid and accurate diagnosis. In this study, we aimed to improve the diagnostic accuracy of AD by presenting a novel method for aortic segmentation in computed tomography images that uses a combination of a transformer and a UNet cascade network with a Zoom-Out and Zoom-In scheme (ZOZI-seg). MethodsThe proposed method segments each compartment of the aorta, comprising the true lumen (TL), false lumen (FL), and thrombosis (TH) using a cascade strategy that captures both the global context (anatomical structure) and the local detail texture based on the dynamic patch size with ZOZI schemes. The ZOZI-seg model has a two-stage architecture using both a “3D transformer for panoptic context-awareness” and a “3D UNet for localized texture refinement.” The unique ZOZI strategies for patching were demonstrated in an ablation study. The performance of our proposed ZOZI-seg model was tested using a dataset from Asan Medical Center and compared with those of existing models such as nnUNet and nnFormer. ResultsIn terms of segmentation accuracy, our method yielded better results, with Dice similarity coefficients (DSCs) of 0.917, 0.882, and 0.630 for TL, FL, and TH, respectively. Furthermore, we indirectly compared our model with those in previous studies using an external dataset to evaluate its robustness and generalizability. ConclusionsThis approach may help in the diagnosis and treatment of AD in different clinical situations and provide a strong basis for further research and clinical applications.

Mapping of Alzheimer’s disease related data elements and the NIH Common Data Elements

BackgroundAlzheimer’s Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer’s Coordinating Center (NACC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas.MethodTo better understand how AD-related data elements in these resources are interoperable with each other, we leverage different representation models to map data elements from different resources: NACC to ADNI, NACC to NIH CDE, and ADNI to NIH CDE. We explore bag-of-words based and word embeddings based models (Word2Vec and BioWordVec) to perform the data element mappings in these resources.ResultsThe data dictionaries downloaded on November 23, 2021 contain 1,195 data elements in NACC, 13,918 in ADNI, and 27,213 in NIH CDE Repository. Data element preprocessing reduced the numbers of NACC and ADNI data elements for mapping to 1,099 and 7,584 respectively. Manual evaluation of the mapping results showed that the bag-of-words based approach achieved the best precision, while the BioWordVec based approach attained the best recall. In total, the three approaches mapped 175 out of 1,099 (15.92%) NACC data elements to ADNI; 107 out of 1,099 (9.74%) NACC data elements to NIH CDE; and 171 out of 7,584 (2.25%) ADNI data elements to NIH CDE.ConclusionsThe bag-of-words based and word embeddings based approaches showed promise in mapping AD-related data elements between different resources. Although the mapping approaches need further improvement, our result indicates that there is a critical need to standardize CDEs across these valuable AD research resources in order to maximize the discoveries regarding AD pathophysiology, diagnosis, and treatment that can be gleaned from them.