Treatment Of Alzheimer's Disease Research Articles

Evaluation of Anti-Alzheimer's Potential of Azo-Stilbene-Thioflavin-T derived Multifunctional Molecules: Synthesis, Metal and Aβ Species Binding and Cholinesterase Activity.

Inhibition of amyloid β (Aβ) aggregation and cholinesterase activity are two major therapeutic targets for Alzheimer's disease (AD). Multifunctional Molecules (MFMs) specifically designed to address other contributing factors, such as metal ion induced abnormalities, oxidative stress, toxic Ab aggregates etc. are very much required. Several multifunctional molecules have been developed using different molecular scaffolds. Reported herein is a new series of four MFMs based on ThT, Azo-stilbene and metal ion chelating pockets. The synthesis, characterization, and metal chelation ability for [Cu(II) and Zn(II)] are presented herein. Furthermore, we explored their multifunctionality w.r.t. to their (i) recognition of Aβ aggregates and monomeric form, (ii) utility in modulating the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) ex-vivo staining of amyloid plaques in 5xFAD mice brain sections, (iv) ability to scavenge free radicals and (v) ability to inhibit cholinesterase activity. Molecular docking studies were also performed with Aβ peptides and acetylcholinesterase enzyme to understand the observed inhibitory effect on activity. Overall, the studies presented here establish the multifunctional nature of these molecules and qualify them as promising candidates for furthermore investigation in the quest for finding Alzheimer's disease treatment.

Plasma exchange with albumin replacement for Alzheimer's disease treatment induced changes in serum and cerebrospinal fluid inflammatory mediator levels.

There is extensive literature indicating that inflammatory pathways are affected in Alzheimer's disease (AD). We examined whether plasma exchange with albumin replacement (PE-Alb) can impact the inflammatory status of AD patients and alter the relationship between inflammatory mediators and cognitive measures. Serum and cerebrospinal fluid (CSF) samples from 142 AD patients participating in the AMBAR trial (14-month schedule of PE-Alb treatment vs. placebo [sham PE-Alb]) were analyzed for changes from baseline for 19 inflammatory mediators (6 inflammatory cytokines, 9 chemokines, and 4 vascular injury indicators) at representative time points across the AMBAR study (lasting effects) as well as in pre- versus post-PE-Alb procedure (acute effects). Association between mediator changes and clinical outcomes reported in the AMBAR study (cognitive, functional, behavioral function, and global change tests) was assessed. PE-Alb significantly reduced IFN-γ, eotaxin, MIP-1α and ICAM-1 levels in serum, and eotaxin-3 and MIP-1β levels in CSF, at various time points during treatment (p < 0.05; false discovery rate-corrected). Vascular injury indicators were the mediators mostly affected by post- versus pre-PE-Alb level reduction. Increased serum MIP-1α levels were associated with worsening in ADAS-Cog, CDR-sb, and ADCS-CGIC scores in the placebo group, but not in the PE-Alb-treated group. Peripheral intervention could affect AD by reducing inflammatory mediators in both peripheral and central compartments. Changes in MIP-1α due to PE-Alb were associated with changes in clinical outcomes.

Effect of Nattokinase in D-galactose- and Aluminum Chloride-induced Alzheimer's Disease Model of Rat.

Alzheimer's disease (AD) is the most common form of dementia worldwide. Nattokinase is a serine protease extracellularly produced by natto, a fermented product of Bacillus subtilis var. natto. In this study, we investigated the therapeutic effects of nattokinase in a rat model of AD induced by aluminum and D-galactose. Forty Wistar rats were randomly divided into four groups: normal, vehicle, and orally administered nattokinase (NK65 and NK130 groups). Except for the normal group, all groups were treated with AlCl3 and D-galactose for 10 weeks. The NK65 and NK130 groups additionally received 65 mg/kg/day and 130 mg/kg/day nattokinase, respectively. We analyzed β-amyloid levels in the cerebrospinal fluid (CSF), and the spatial reference test was evaluated using the Morris water maze test. After the Morris water maze test, rats of all groups were subjected to micro-computed tomography (μCT) to assess constructional changes in the brain. Aluminum concentration and β-amyloid levels were analyzed by histochemical staining in all brain tissues. Oral administration of nattokinase in the AD rat model increased free-form β-amyloid levels in the CSF and improved aluminum and amyloid plaque accumulation in the brain. Brain μCT images showed enhanced brain volume with fewer constructional changes after treatment with nattokinase. In the behavioral tests, both the escape latency time in the spatial reference test and the time taken to cross the platform area in the spatial probe test improved partially. The results suggest that nattokinase has potential therapeutic applications in the treatment of AD.

A microglia-containing 3D human brain organoid for studying HSV-1-induced Alzheimer’s disease

As a progressive neurodegenerative disorder, Alzheimer’s disease (AD) can result in significant memory loss and cognitive deterioration. Several recent studies show that herpes simplex virus type I (HSV-1) is closely related to AD pathology. Microglia, the primary immune cells in the central nervous system, are also shown to play an important role in AD. In this study, we developed a microglia-containing 3-dimensional (3D) human brain organoid from human-induced pluripotent stem cells (hiPSCs) to study the relationship between microglia and HSV-1-induced AD phenotypes. We found that microglia increased the generation of amyloid-β protein (Aβ) and neurofibrillary tangles (NFTs), contributed to neural loss, and enhanced gliosis and neuroinflammation. We also employed shRNA vectors to inhibit certain cytokines related to neuroinflammation and examined the impact on Aβ aggregation. This model can facilitate future research on the treatment of AD regarding microglia and HSV-1.

Identification of mild cognitive impairment using multimodal 3D imaging data and graph convolutional networks

Abstract Objective. Mild cognitive impairment (MCI) is a precursor stage of dementia characterized by mild cognitive decline in one or more cognitive domains, without meeting the criteria for dementia. MCI is considered a prodromal form of Alzheimer's disease (AD). Early identification of MCI is crucial for both intervention and prevention of AD. To accurately identify MCI, a novel multimodal 3D imaging data integration graph convolutional network model is designed in this paper. Approach. The proposed model utilizes 3D-VGGNet to extract three-dimensional features from multimodal imaging data (such as sMRI and FDG-PET), which are then fused into feature vectors as the node features of a population graph. Non-imaging features of participants are combined with the multimodal imaging data to construct a population sparse graph. Additionally, in order to optimize the connectivity of the graph, we employed the Pairwise Attribute Estimation (PAE) method to compute the edge weights based on non-imaging data, thereby enhancing the effectiveness of the graph structure. Subsequently, a population-based graph convolutional network (GCN) integrates the structural and functional features of different modal images into the features of each participant for MCI classification. Main results. Experiments on the ADNI demonstrated accuracies of 98.57%, 96.03%, and 96.83% for the NC-EMCI, NC-LMCI, and EMCI-LMCI classification tasks, respectively. The AUC, specificity, sensitivity, and F1-score are also superior to state-of-the-art models, demonstrating the effectiveness of the proposed model. Furthermore, the proposed model is applied to the ABIDE dataset for autism diagnosis, achieving an accuracy of 91.43% and outperforming the state-of-the-art models, indicating excellent generalization capabilities of the proposed model. Significance. This study demonstrate the proposed model’s ability to integrate multimodal imaging data and its excellent ability to recognize MCI. This will help achieve early warning for AD and intelligent diagnosis of other brain neurodegenerative diseases.

Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β-amyloid Peptide Aggregation.

The aggregation of β-amyloid peptide (Aβ) is associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several therapies aimed at reducing the aggregation of this peptide have emerged as potential strategies for the treatment of AD. This paper describes the design and preparation of new hybrid molecules based on steroids, selenosugars, and [60]fullerene as potential inhibitors of Aβ oligomerization. These moieties were selected based on their antioxidant properties and possible areas of interaction with the Aβ. Cyclopropanations between C60 and malonates bearing different steroid and selenosugar moieties using the Bingel-Hirsch protocol have enabled the synthesis of functionalized molecular hybrids. The obtained derivatives were characterized by physical and spectroscopic techniques. Theoretical calculations for all the selenium compounds were performed using the density functional theory DFT/B3LYP-D3(BJ)/6-311G(2d,p) predicting the most stable conformations of the synthesized derivatives. Relevant geometrical parameters were investigated to relate the stereochemical behavior and the spectroscopic data obtained. The affinity of the compounds for Aβ-peptide was estimated by molecular docking simulation, which predicted an increase in affinity and interactions for Aβ for the hybrids containing the C60 core. In addition, parameters such as lipophilicity, polar surface area, and dipole moment were calculated to predict their potential interaction with membrane cells.

Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases

Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Dihydro-resveratrol ameliorates NLRP3 inflammasome-mediated neuroinflammation via Bnip3-dependent mitophagy in Alzheimer's disease.

Dihydro-resveratrol (DHR), a polyphenol derivative, that has been demonstrated to suppress inflammation-mediated injury. However, it is still unknown whether it has anti-neuroinflammatory and neuroprotective effects, and a therapeutic action in Alzheimer's disease (AD). The anti-inflammatory and anti-Alzheimer's disease actions of dihydro-resveratrol were investigated using lipopolysaccharide (LPS) and AD mice models, and primary microglial cells. The changes in behaviour in mice were detected by the Morris water maze test and open-field test. Flow cytometry assay, western blotting, immunofluorescence assays and co-immunoprecipitation were used to investigate the changes in the NLRP3 inflammasome activation and mitophagy. In this study, in vivo observations indicated that the administration of dihydro-resveratrol (DHR) dramatically restored spatial learning, memory ability, autophagy and mitophagy, attenuated NLRP3 inflammasome activation, neuroinflammation and amyloid precursor protein pathology in LPS mice and AD mice. In addition, the inhibition of autophagy and mitophagy, or the activation of NLRP3 in vivo greatly abolished DHR-generated therapeutic efficacy on neuroinflammation, amyloid precursor protein pathology and cognitive loss. Further examination indicated that the application of DHR after the LPS and ATP exposure significantly inhibited the NLRP3 inflammasome activation, neuroinflammation and enhanced autophagic and mitophagic activation in microglia. Additionally, in vitro results show that DHR protects microglial cells against LPS and ATP-induced cytotoxicity by inhibiting NLRP3 inflammasome through activating Bnip3-dependent mitophagy and ULK phosphorylation. In summary, these findings suggest that dihydro-resveratrol (DHR) possesses potent anti-neuroinflammatory property and can act as a potential therapeutic agent for the treatment of AD.

Brazilian kefir fraction mitigates the Alzheimer-like phenotype in Drosophila melanogaster with β-amyloid overexpression model

Alzheimer’s disease (AD) is a progressive neurodegenerative condition and the primary form of dementia among elderly people. The amyloidogenic hypothesis is the main theory that explains this phenomenon and describes the extracellular accumulation of amyloid beta (Aβ) peptides. Model organisms such as Drosophila melanogaster have been utilized to improve the understanding of this disease and its treatment. This study evaluated the effects of peptide and metabolic fractions of Brazilian kefir on a strain of D. melanogaster that expresses human Aβ peptide 1–42 in the eye. The parameters assessed included ommatidial organization, vacuole area, retinal thickness, and Aβ peptide quantification. The present study revealed that the fractions, particularly the peptidic fraction, significantly reduced the vacuole area and increased the retina thickness in treated flies, indicating an improvement in neurodegeneration phenotype. The peptidic fraction was also found to alter Aβ aggregation dynamics, inhibiting Aβ fibril formation, as revealed by dynamic light scattering. This study demonstrated that kefir fractions, particularly the peptidic fraction < 10 kDa, have the potential to regulate Aβ aggregation and alleviate neurodegeneration in a Drosophila melanogaster AD-like model. These findings suggest that kefir fractions could be viable for the bioprospection of novel drug prototypes for AD treatment, providing valuable insights into strategies targeting Aβ aggregation and neurodegeneration in AD.

Longitudinal and Multi-Kingdom Gut Microbiome Alterations in a Mouse Model of Alzheimer's Disease.

Gut microbial dysbiosis, especially bacteriome, has been implicated in Alzheimer's disease (AD). However, nonbacterial members of the gut microbiome in AD, such as the mycobiome, archaeome, and virome, are unexplored. Here, we perform higher-resolution shotgun metagenomic sequencing on fecal samples collected longitudinally from a mouse model of AD to investigate longitudinal and multi-kingdom gut microbiome profiling. Shotgun metagenomic sequencing of fecal samples from AD mice and healthy mice returns 41,222 bacterial, 414 fungal, 1836 archaeal, and 1916 viral species across all time points. The ecological network pattern of the gut microbiome in AD mice is characterized by more complex bacterial-bacterial interactions and fungal-fungal interactions, as well as simpler archaeal-archaeal interactions and viral-viral interactions. The development of AD is accompanied by multi-kingdom shifts in the gut microbiome composition, as evidenced by the identification of 1177 differential bacterial, 84 differential fungal, 59 differential archaeal, and 10 differential viral species between healthy and AD mice across all time points. In addition, the functional potential of the gut microbiome is partially altered in the development of AD. Collectively, our findings uncover longitudinal and multi-kingdom gut microbiome alterations in AD and provide a motivation for considering microbiome-based therapeutics during the prevention and treatment of AD.

The Role of circRNAs in the Pathological Mechanisms of Alzheimer's Disease and May Serve as Potential Biomarkers.

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia in the elderly, and the mechanisms of AD have not been fully defined. Circular RNAs (circRNAs), covalently closed RNAs produced by reverse splicing, have critical effects in the pathogenesis of AD. CircRNAs participate in production and clearance of Aβ and tau, regulate neuroinflammation, synaptic plasticity and the process of apoptosis and autophagy, indicating that circRNAs may be alternative biomarkers and therapeutic targets. Our review summarizes the functions of circRNAs in the progression and development of AD, which provide insights into the prospect of circRNAs in the diagnosis and treatment of AD.

Cationic Surface Charge Engineering of Recombinant Transthyretin Remarkably Increases the Inhibitory Potency Against Amyloid β-Protein Fibrillogenesis.

The deposition of amyloid β-protein (Aβ) in the brain is the main pathogenesis of Alzheimer's disease (AD). The development of potent inhibitors against Aβ aggregation is one of the effective strategies to combat AD. Endogenous transthyretin (TTR) can inhibit Aβ fibrillization via hydrophobic interactions, but its weak inhibitory potency hinders its application in AD therapy. Here, different recombinant TTRs were designed by cationic surface charge engineering. Compared with TTR, all positively charged recombinant TTRs showed enhanced capability in inhibiting Aβ aggregation, especially the recombinant protein obtained by mutating the acidic amino acid in TTR to arginine (TTR-nR) exhibited excellent inhibitory effect. Among them, TTR-7R remarkably increased the inhibitory potency against Aβ, which could effectively inhibit Aβ40 fibrillization at a very low concentration (0.5 μM). In addition, TTR-7R increased cultured cell viability from 62% to 89%, scavenged amyloid plaques in AD nematodes, and prolonged nematode lifespan by 5 d at 2 μM. Thermodynamic studies demonstrated that TTR-7R, enriching in positive charges, presented hydrophobic interactions and enhanced electrostatic interactions with Aβ40, leading to a significantly enhanced inhibitory capacity of TTR-7R. The research provided insights into the development of efficient recombinant protein inhibitors for AD treatment.

Metformin Mitigates Trimethyltin-Induced Cognition Impairment and Hippocampal Neurodegeneration

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions.

Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.

The perturbed structure and function of mitochondria-associated membranes (MAM), instead of the amyloid cascade, have been gradually proposed to play a basic role in the pathogenesis of Alzheimer's disease (AD). Notably, autophagy inhibition is one of the main mechanisms of MAM dysfunction and plays an important role in neuronal injury. However, the upstream molecular mechanism underlying the MAM dysfunctions remains elusive. Here, we defined an unexpected and critical role of connexin43 (Cx43) in regulating the MAM structure. The expression levels of Cx43 and mitofusin-2 (MFN2, the MAM biomarker) increase significantly in 9-month-old APPswe/PS1dE9 double-transgenic AD model mice, and there is an obvious colocalization relationship. Moreover, both AD mice and cells lacking Cx43 exhibit an evident reduction in the MAM contact sites, which subsequently promotes the conversion from microtubule-associated protein 1 light-chain 3B I (LC3B-I) to LC3B-II via inhibition mTOR-dependent pathway and then initiates the generation of autophagosomes. Autophagosome formation ultimately promotes β-amyloid (Aβ) clearance and attenuates Aβ-associated pathological changes in AD, mainly including astrogliosis and neuronal apoptosis. Our findings not only reveal a previously unrecognized effect of Cx43 on MAM upregulation but also highlight the major player of MAM-induced autophagy inhibition in Cx43-facilitated AD pathogenesis, providing a novel insight into the alternative therapeutic strategies for the early treatment of AD.

Licochalcone A Ameliorates Cognitive Dysfunction in an Alzheimer's Disease Model by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis.

Endoplasmic reticulum (ER) stress-induced neurodegeneration has been considered an underlying cause of Alzheimer disease (AD). Here, we investigated the beneficial effects of licochalcone A (Lico A), a valuable flavonoid of the root of the Glycyrrhiza species, against cognitive impairment in AD by regulating ER stress. The triple transgenic mouse AD models were used and were administrated 5 or 15mg/kg Lico A. Cognitive deficits, Aβ deposition, ER stress, and neuronal apoptosis were determined using Morris Water Maze test, probe trial, immunofluorescence staining, western blotting, and TUNEL staining. To investigate the mechanisms of how Lico A exerts anti-AD effects, primary hippocampal neurons were isolated from the AD model mice and treated with Lico A, salubrinal, an eIF2α phosphatase inhibitor, ML385, a Nrf2 inhibitor, or LY294002, an inhibitor of PI3K. Pharmacokinetics and toxicity of Lico A (15mg/kg) in AD mice were evaluated. We found that Lico A improved cognitive impairment, decreased Aβ plaques, inhibited ER stress, and reduced neuronal apoptosis in the hippocampus and cortex of AD mice. Treatment with Lico A in primary hippocampal neurons exerted the same effects as it did in vivo. Additionally, cotreatment with ML385 or LY294002 significantly impeded the effects of Lico A against ER stress. Moreover, 15mg/kg Lico A had a good bioavailability and low toxicity in AD mice. Our results demonstrated that Lico A ameliorates ER stress-induced neuronal apoptosis by inhibiting PERK/eIF2α/ATF4/CHOP signaling, suggesting the therapeutic potential of Lico A in AD treatment.

Insights on the Characteristics and Therapeutic Potential of Mesenchymal Stem Cell-derived Exosomes for Mitigation of Alzheimer's Disease's Pathogenicity: A Systematic Review.

Alzheimer's disease (AD) remains a progressive neurodegenerative disease with no cure. Treatment of AD relies on administering drugs that only subside the symptoms. In recent studies, mesenchymal stem cell (MSC)-exosomes have been marked to possess therapeutic potential for treating AD. This study aims to systematically review and analyse findings that focus on the isolation, characterisation, and sources of MSC-derived exosomes used to unravel the therapeutic potential of these exosomes targeting AD using in vitro and in vivo models. It is hypothesised that MSC-exosomes exhibit high therapeutic potential for AD treatment by exerting various modes of action. PubMed, Scopus, and Medline were used to find relevant published works from January 2016 until December 2020, using assigned keywords including "Alzheimer's disease", "secretome", and "exosomes". Only research articles meeting the predefined inclusion/exclusion criteria were selected and analysed. The risk of bias was assessed using the Office of Health Assessment and Translation tool (OHAT). A total of 17 eligible in vivo and in vitro studies were included in this review. Bone marrow-derived stem cells (BMSCs) were the most used source for exosome isolation, even though studies on exosomes from adipose-derived stem cells (ADSCs) and human umbilical cord stem cells (HUCSCs) provide more information on the characteristics. When the risk of bias was assessed, the studies presented various levels of biases. Notably, the in vitro and in vivo studies revealed neuroprotective properties of MSC-exosomes through different modes of action to alleviate AD pathology. Our review discovered that most MSC exosomes could degrade Aβ plaques, enhance neurogenesis, extenuate neuroinflammatory response through microglial activation, regulate apoptosis and reduce oxidative stress. Delivery of exosomal micro-RNAs was also found to reduce neuroinflammation. Findings from this review provided convincing systematic evidence highlighting the therapeutic properties of MSC-derived exosomes as a prospective source for cell-free (acellular) therapy in treating AD.

Dietary Flavonoid Chrysin Functions as a Dual Modulator to Attenuate Amyloid-β and Tau Pathology in the Models of Alzheimer's Disease.

Growing evidence indicates that healthy diets are associated with a slower progression of Alzheimer's disease (AD). Flavonoids are among the most abundant natural products in diets beneficial to AD, such as the Mediterranean diet. However, the effect and mechanism of these dietary flavonoids on AD remains incompletely understood. Here, we found that a representative dietary natural flavonoid, chrysin (Chr), significantly ameliorated cognitive impairment and AD pathology in APP/PS1 mice. Furthermore, mechanistic studies showed that Chr significantly reduced the levels of amyloid-β (Aβ) and phosphorylated tau (p-tau), along with dual inhibitory activity against β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase 3β (GSK3β). Moreover, the effect of Chr was further confirmed by EW233, a structural analog of Chr that exhibited an improved pharmacokinetic profile. To further verify the role of Chr and EW233, we utilized our previously established chimeric human cerebral organoid (chCO) model for AD, in which astrogenesis was promoted to mimic the neuron-astrocyte ratio in human brain tissue, and similar dual inhibition of Aβ and p-tau was also observed. Altogether, our study not only reveals the molecular mechanisms through which dietary flavonoids, such as Chr, mitigate AD pathology, but also suggests that identifying a specific constituent that mimics some of the benefits of these healthy diets could serve as a promising approach to discover new treatments for AD.

Artemisiae Iwayomogii Herba mitigates excessive neuroinflammation and Aβ accumulation by regulating the pro-inflammatory response and autophagy-lysosomal pathway in microglia in 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) presents a growing societal challenge, driven by an aging population. It is characterized by neurodegeneration linked to β-amyloid (Aβ) and tau protein aggregation. Reactive glial cell-mediated neuroinflammation exacerbates disease progression by facilitating the accumulation of Aβ and impairing its clearance, thus highlighting potential therapeutic targets. Aerial parts of Artemisia iwayomogi (AIH), a kind of mugwort, has been consumed as a medicinal herb in East Asia for relieving inflammation-related diseases. Previously, AIH was found to exert potent inhibitory effects on neuroinflammation. This study aimed to examine whether AIH mitigates AD pathogenesis by regulating neuroinflammation and reducing Aβ deposition. AIH treatment to primary mixed glial cultures attenuated the pro-inflammatory responses evoked by Aβ stimulation. When treated to 5 × familial AD (5xFAD) mice, AIH improved learning and cognitive ability and reduced Aβ burden in the brain. AIH suppressed glial overactivation, as well as inhibited the expressions of pro-inflammatory mediators in the brain. Moreover, AIH regulated AKT signaling and elevated the expression of autophagy-lysosomal mediators in vitro. It was confirmed that lysosome-associated membrane protein 1 (LAMP1) was increased in the Aβ-associated microglia in the mouse hippocampus. Finally, it was observed that tau phosphorylation was alleviated, and synaptic protein expression was increased in AIH-treated 5xFAD mice. Overall, this study demonstrated that AIH ameliorated excessive neuroinflammation and Aβ accumulation by regulating microglial activation and autophagy-lysosomal pathway, thereby suggesting AIH as a promising therapeutic candidate for AD treatment.

Near-infrared light stimulation regulates neural oscillation and memory behavior of mice with Alzheimer's disease.

Photobiomodulation (PBM) is a non-invasive neuromodulation technique for the brain. Low-intensity near-infrared light (1-500 mw) has demonstrated the ability to improve memory in Alzheimer's disease (AD) model mice, suggesting its potential for AD treatment. However, the impact of PBM on neural oscillations in the hippocampal region affected by AD remains unknown. In this study, AD model mice were subjected to PBM for 60 days and then tested using novel object recognition behavior (NOR) experiments. During behavioral experiments, local field potential signals (LFP) of the mice was recorded using a single electrode in the CA1 region to analyze memory ability and neural oscillation characteristics. The results revealed that mice stimulated with PBM exhibited significantly higher new object differentiation indices compared to the Sham group (p < 0.01). Furthermore, PBM stimulation led to a significant increase in relative power and sample entropy of theta and gamma bands (p < 0.01). The coupling intensities of θ-low-γ and θ-high-γ were also significantly higher in the PBM group compared to the Sham group (p < 0.01). In conclusion, these findings suggest that PBM may improve memory ability in AD mice through regulation of neural oscillation characteristics, providing a theoretical basis for utilizing PBM as a treatment modality for Alzheimer's disease.

Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors Based on the Pyridyl–Pyridazine Moiety for the Potential Treatment of Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1H NMR, and 13C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and -13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer’s disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors.