Alzheimer's Disease Cell Model Research Articles

Neuroprotection and Mechanism of Gas-miR36-5p from Gastrodia elata in an Alzheimer's Disease Model by Regulating Glycogen Synthase Kinase-3β.

Alzheimer's disease (AD) is currently the most common neurodegenerative disease. Glycogen synthase kinase 3β (GSK-3β) is a pivotal factor in AD pathogenesis. Recent research has demonstrated that plant miRNAs exert cross-kingdom regulation on the target genes in animals. Gastrodia elata (G. elata) is a valuable traditional Chinese medicine that has significant pharmacological activity against diseases of the central nervous system (CNS). Our previous studies have indicated that G. elata-specific miRNA plays a cross-kingdom regulatory role for the NF-κB signaling pathway in mice. In this study, further bioinformatics analysis suggested that Gas-miR36-5p targets GSK-3β. Through western blot, RT-qPCR, and assessments of T-AOC, SOD, and MDA levels, Gas-miR36-5p demonstrated its neuroprotective effects in an AD cell model. Furthermore, Gas-miR36-5p was detected in the murine brain tissues. The results of the Morris water maze test and western blot analysis provided positive evidence for reversing the learning deficits and hyperphosphorylation of Tau in AD mice, elucidating significant neuroprotective effects in an AD model following G. elata RNA administration. Our research emphasizes Gas-miR36-5p as a novel G. elata-specific miRNA with neuroprotective properties in Alzheimer's disease by targeting GSK-3β. Consequently, our findings provide valuable insights into the cross-kingdom regulatory mechanisms underlying G. elata-specific miRNA, presenting a novel perspective for the treatment of Alzheimer's disease.

Saxagliptin reduces the injury of Alzheimer's disease cell model by down-regulating the expression of miR-483-5p

Saxagliptin reduces the injury of Alzheimer's disease cell model by down-regulating the expression of miR-483-5p

MiR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3′-untranslated region (3′ UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model.

Hyperphosphorylation of Tau is one of the important pathological features of Alzheimer's disease (AD). Therefore, studying the mechanisms behind Tau hyperphosphorylation is crucial in exploring the pathogenesis of neurological damage in AD. In this study, after the establishment of rat models of AD, quantitative phosphoproteomics and proteomics were performed to identify proteins, showing that phosphorylation of microtubule associated protein 1A (MAP 1A) was lower in the model group. Western blot confirmed the changes of MAP 1A in the SD rats, APP/PS1 transgenic mice and cell AD models. To further study the molecular mechanism of recombinant MAP 1A phosphorylation affecting Tau phosphorylation, interfering siRNA-MAP 1A and protein immunoprecipitation reaction analysis were performed in AD cell models. Cyclin-dependent kinase 5 (CDK5) showed reduced binding to MAP 1A and increased binding to Tau, resulting in a decrease in phosphorylated MAP 1A (p-MAP 1A) and an increase in phosphorylated Tau (p-Tau), and MAP 1A silencing promoted binding of CDK5-Tau and increased Tau phosphorylation, thereby reducing the cell survival rate. In summary, we found that p-MAP 1A downregulation associated with p-Tau upregulation was due to their altered binding forces to CDK5, and MAP 1A could enhance autophosphorylation by competitive binding to CDK5 and antagonise Tau phosphorylation. This leads to neuronal protection and reducing tissue damage levels in AD, which can help better understand the mechanisms of AD pathogenesis.

Visualization of the elevated levels of hypochlorous acid in Alzheimer's disease with a ruthenium(II) complex-based luminescence probe

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that devastatingly affects people's lives. Accumulating evidence indicates that the pathological progression of AD is inseparably connected with hypochlorous acid (HClO). However, further exploring the biological function remains an open challenging due to a lack of effective tools to image HClO in AD brains. To this end, a ruthenium(II) luminescence probe, Ru–HClO, is developed for quantitative detection and visualization of HClO in nerve cells and AD brains. Ru–HClO shows quenched luminescence due to the PET process (excited electron transfer from Ru(II) center to diaminomaleonitrile) and the CN bond isomerization in the excited state. The HClO-triggered specific cleavage reaction with Ru–HClO cleaves the CN bond to form highly luminescent Ru–COOH. Ru–HClO shows rapid response speed, high sensitivity and selectivity, excellent biocompatibility, which makes the probe to be applied to semi-quantitative analysis of HClO in nerve cells and high-throughput screening of anti-AD drugs in the AD cell model. Moreover, using Ru–HClO as a probe, present work further validated that the elevated levels of HClO secretion were accompanied by the AD progressed. These findings may provide valuable results for figuring out the biological roles that HClO played in AD but also for accelerating anti-AD therapeutic discovery.

Mechanism of albiflorin in improvement of Alzheimer's disease based on network pharmacology and in vitro experiments

This study aimed to explore the mechanism of albiflorin in the treatment of Alzheimer's disease(AD) based on network pharmacology, molecular docking, and in vitro experiments. Network pharmacology was used to predict the potential targets and pathways of albiflorin against AD, and molecular docking technology was used to verify the binding affinity of albiflorin to key target proteins. Finally, the AD cell model was induced by Aβ_(25-35) in rat pheochromocytoma(PC12) cells and intervened by albiflorin to validate core targets and pathways. The results of network pharmacological analysis showed that albiflorin acted on key targets such as mitogen-activated protein kinase-1(MAPK1 or ERK2), albumin(ALB), epidermal growth factor receptor(EGFR), caspase-3(CASP3), and sodium-dependent serotonin transporter(SLC6A4), and signaling pathways such as MAPK, cAMP, and cGMP-PKG. The results of molecular docking showed that albiflorin had strong binding affinity to MAPK1(ERK2). In vitro experiments showed that compared with the blank group, the model group showed decreased cell viability, decreased expression level of B-cell lymphoma 2(Bcl-2), increased Bcl-2-associated X protein(Bax), and reduced phosphorylation level of extracellular signal-regulated kinase 1/2(ERK1/2) and the relative expression ratio of p-ERK1/2 to ERK1/2. Compared with the model group, the albiflorin group showed potentiated cell viability, up-regulated expression of Bcl-2, down-regulated Bax, and increased phosphorylation level of ERK1/2 and the relative expression ratio of p-ERK1/2 to ERK1/2. These results suggest that the mechanism of albiflorin against AD may be related to its activation of the MAPK/ERK signaling pathway and its inhibition of neuronal apoptosis.

PPARɑ Ligand Caudatin Improves Cognitive Functions and Mitigates Alzheimer's Disease Defects By Inducing Autophagy in Mice Models.

The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aβ) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aβ and phospho-Tau in AD. Peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that can activate autophagy, and transcriptionally regulate transcription factor EB (TFEB) which is a key regulator of ALP. This suggests that targeting PPARα, to reduce ALP impairment, could be a viable strategy for AD therapy. In this study, we investigated the anti-AD activity of Caudatin, an active constituent of Cynanchum otophyllum (a traditional Chinese medicinal herb, Qing Yang Shen; QYS). We found that Caudatin can bind to PPARα as a ligand and augment the expression of ALP in microglial cells and in the brain of 3XTg-AD mice model. Moreover, Caudatin could activate PPARα and transcriptionally regulates TFEB-augmented lysosomal degradation of Aβ and phosphor-Tau aggregates in AD cell models. Oral administration of Caudatin decreased AD pathogenesis and ameliorated the cognitive dysfunction in 3XTg-AD mouse model. Conclusively, Caudatin can be a potential AD therapeutic agent via activation of PPARα-dependent ALP.

Physalin B Reduces Tau Phosphorylation and Cell Apoptosis in HEK293 Cells by Activating FoxO1.

Physalin B (PB) is one of the main active compounds of Solanaceae plants, with a wide range of biological activities. PB reportedly has the potential to treat Alzheimer's disease (AD). In this study, we investigated the effect of PB on Tau phosphorylation and cell apoptosis using Tau-expressing HEK293 cells (HEK293/Tau) as a cellular model. The optimum concentration of PB to treat HEK293/Tau cells was determined using the CCK-8 assay. Additionally, the expression of FoxO1, Tau-5, p-Tau (T231, S262, and S404), ERK, p-ERK, GSK-3β, and p-GSK-3β was detected using western blotting to determine the effect of PB on Tau phosphorylation. The apoptosis rate was detected using flow cytometry, and the expression of Bax and Bcl-2 was detected using western blotting and verified using real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, cells were transfected with FoxO1 siRNA to downregulate FoxO1 expression, and the expression of the above-mentioned proteins was detected to verify the effect of PB on Tau phosphorylation and cell apoptosis. After 24 h of PB treatment, the phosphorylation levels of Tau at S404, S262, and T231 sites decreased significantly, and the activities of GSK-3β and ERK were inhibited. PB also reduced cell apoptosis by reducing the expression of Bax and increasing the expression of Bcl-2. In addition, PB decreased Tau phosphorylation and cell apoptosis by upregulating FoxO1. The natural compound PB exhibited a protective effect in the AD cell model by increasing FoxO1 expression and reducing Tau phosphorylation and cell apoptosis.

Resveratrol alleviates amyloid β-induced neuronal apoptosis, inflammation, and oxidative and endoplasmic reticulum stress by circ_0050263/miR-361-3p/PDE4A axis during Alzheimer's disease.

Resveratrol (Res) has been identified to reduce neurodegeneration. Circular RNAs (circRNAs) are stable noncoding RNAs that are considered to be ideal biomarkers for molecular targeting treatment. Here, this study focused on investigating the function and relationship of circ_0050263 and Res in Alzheimer's Disease (AD). Human neuroblastoma cell line SK-N-SH was exposed to amyloid-β (Aβ) to induce AD cell model in vitro. Cell viability, apoptosis, and inflammatory reaction were evaluated by CCK-8 assay, flow cytometery, and ELISA analysis. The oxidative stress and endoplasmic reticulum stress (ERS) were determined by detecting related markers. Levels of genes and proteins were detected by qRT-PCR and Western blot. Dual-luciferase reporter assay was adopted to verify the binding between miR-361-3p and circ_0050263 or PDE4A (Phosphodiesterase 4A). Subsequently, we found that Res treatment alleviated Aβ-induced apoptosis, inflammatory response, oxidative stress, and ERS in SK-N-SH cells. Circ_0050263 is a stable circRNA, which was increased by Aβ, but decreased by Res in SK-N-SH cells. Circ_0050263 overexpression reversed Res-induced neuroprotective effects. Mechanistically, circ_0050263 acted as a sponge for miR-361-3p, which targeted PDE4A. Circ_0050263 silencing abated Aβ-induced neuronal injury, which were counteracted by following PDE4A overexpression. Moreover, PDE4A upregulation could attenuate Res-mediated neuroprotective effects. In all, Res alleviated Aβ-induced neuronal apoptosis, inflammation, oxidative stress, and ERS via circ_0050263/miR-361-3p/PDE4A axis, providing new insights for AD therapy.

MKP-1 regulates the inflammatory activation of microglia against Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia in elderly people. Microglia-mediated neuroinflammation plays an important role in AD pathogenesis, so modulation of neuroinflammation has emerged as an essential therapeutic method to improve AD. The current study aims to investigate whether MKP-1 can regulate microglia phenotype and inflammatory factor release in AD and explore its possible mechanisms. Amyloid precursor protein/PS1 double transgenic mice and wild-type mice were selected to study the locations of microglia and amyloid-β (Aβ) plaques in different regions of mice brains. Changes in MKP-1 of microglia were detected using AD model mice and AD model cells. Changes in phenotype and the release of inflammatory factors within immortalized BV2 murine microglia were investigated by regulating the expression of MKP-1. The distribution of microglia and Aβ plaques in the AD brain was region-specific. MKP-1 expression was downregulated in AD mice, and in vitro, with increasing Aβ concentrations, MKP-1 expression was reduced. MKP-1 over-expression increased M2 microglia but decreased M1 microglia accompanied by changes in inflammatory factors and inhibition of MKP-1 yielded the opposite result. MKP-1 regulated microglia phenotype and inflammatory factor release in AD through modulation of the p38 signaling pathway.

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Aizheimer's disease using network pharmacology approach and in vitro experimental validation

AimsTo explore the new indications and key mechanism of Bazi Bushen capsule (BZBS) by network pharmacology and in vitro experiment. MethodsThe ingredients library of BZBS was constructed by retrieving multiple TCM databases. The potential target profiles of the components were predicted by target prediction algorithms based on different principles, and validated by using known activity data. The target spectrum of BZBS with high reliability was screened by considering the source of the targets and the node degree in compound-target (C-T) network. Subsequently, new indications for BZBS were predicted by disease ontology (DO) enrichment analysis and initially validated by GO and KEGG pathway enrichment analysis. Furthermore, the target sets of BZBS acting on AD signaling pathway were identified by intersection analysis. Based on STRING database, the PPI network of target was constructed and their node degree was calculated. Two Alzheimer's disease (AD) cell models, BV-2 and SH-SY5Y, were used to preliminarily verify the anti-AD efficacy and mechanism of BZBS in vitro. ResultsIn total, 1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula, and 1320 BZBS targets with high confidence were predicted. Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treatment of AD. GO and KEGG enrichment results provide a preliminary verification of this point. Among them, 113 functional targets of BZBS belong to AD pathway. A PPI network containing 113 functional targets and 1051 edges for the treatment of AD was constructed. In vitro experiments showed that BZBS could significantly reduce the release of TNF-α and IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells, which may be related to the regulation of ERK1/2/NF-κB signaling pathway. BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells, significantly increased mitochondrial membrane potential, reduced the expression of Caspase3 active fragment and PSEN1, and increased the expression of IDE. This may be related to the regulation of GSK-3β/β-catenin signaling pathway. ConclusionsBZBS formula has a potential use in the treatment of AD, which is achieved through regulation of ERK1/2, NF-κB signaling pathways, and GSK-3β/β-catenin signaling pathway. Furthermore, the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action. The study lays a foundation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

Octadecaneuropeptide Ameliorates Cognitive Impairments Through Inhibiting Oxidative Stress in Alzheimer's Disease Models.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β peptide (Aβ) deposition. Aβ accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. To profile the potential effects of ODN on AD. We established a mouse model of AD via microinjection of Aβ in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of ODN on AD. DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aβ generation by downregulating amyloidogenic AβPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aβ-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2+ and cleaved caspase-3 levels in Aβ-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aβ-treated mice. These results suggest that ODN may exert a potent neuroprotective effect against Aβ-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD.

Chrysophanol exerts a protective effect against Aβ25-35-induced Alzheimer's disease model through regulating the ROS/TXNIP/NLRP3 pathway.

The primary pathogenic factors of Alzheimer's disease (AD) have been identified as oxidative stress, inflammatory damage, and apoptosis. Chrysophanol (CHR) has a good neuroprotective effect on AD, however, the potential mechanism of CHR remains unclear. In this study, we focused on the ROS/TXNIP/NLRP3 pathway to determine whether CHR regulates oxidative stress and neuroinflammation. D-galactose and Aβ25-35 combination were used to build an in vivo model of AD, and the Y-maze test was used to evaluate the learning and memory function of rats. Morphological changes of neurons in the rat hippocampus were observed using hematoxylin and eosin (HE) staining. AD cell model was established by Aβ25-35 in PC12 cells. The DCFH-DA test identified reactive oxygen species (ROS). The apoptosis rate was determined using Hoechst33258 and flow cytometry. In addition, the levels of MDA, LDH, T-SOD, CAT, and GSH in serum, cell, and cell culture supernatant were detected by colorimetric method. The protein and mRNA expressions of the targets were detected by Western blot and RT-PCR. Finally, molecular docking was used to further verify the in vivo and in vitro experimental results. CHR could significantly improve learning and memory impairment, reduce hippocampal neuron damage, and reduce ROS production and apoptosis in AD rats. CHR could improve the survival rate, and reduce the oxidative stress and apoptosis in the AD cell model. Moreover, CHR significantly decreased the levels of MDA and LDH, and increased the activities of T-SOD, CAT, and GSH in the AD model. Mechanically, CHR significantly reduced the protein and mRNA expression of TXNIP, NLRP3, Caspase-1, IL-1β, and IL-18, and increase TRX. CHR exerts neuroprotective effects on the Aβ25-35-induced AD model mainly by reducing oxidative stress and neuroinflammation, and the mechanism may be related to ROS/TXNIP/NLRP3 signaling pathway.

Butyrate acts as a G-protein-coupled receptor ligand that prevents high glucose-induced amyloidogenesis in N2a cells through the protein kinase B/glycogen synthase kinase-3β pathway.

Butyrate acts as a G-protein-coupled receptor ligand that prevents high glucose-induced amyloidogenesis in N2a cells through the protein kinase B/glycogen synthase kinase-3β pathway.

Membrane lipid remodeling modulates γ-secretase processivity

Imbalances in the amounts of amyloid-β peptides (Aβ) generated by the membrane proteases β- and γ-secretase are considered as a trigger of Alzheimer's disease (AD). Cell-free studies of γ-secretase have shown that increasing membrane thickness modulates Aβ generation but it has remained unclear if these effects are translatable to cells. Here we show that the very long-chain fatty acid erucic acid (EA) triggers acyl chain remodeling in AD cell models, resulting in substantial lipidome alterations which included increased esterification of EA in membrane lipids. Membrane remodeling enhanced γ-secretase processivity, resulting in the increased production of the potentially beneficial Aβ37 and/or Aβ38 species in multiple cell lines. Unexpectedly, we found that the membrane remodeling stimulated total Aβ secretion by cells expressing WT γ-secretase but lowered it for cells expressing an aggressive familial AD mutant γ-secretase. We conclude that EA-mediated modulation of membrane composition is accompanied by complex lipid homeostatic changes that can impact amyloidogenic processing in different ways and elicit distinct γ-secretase responses, providing critical implications for lipid-based AD treatment strategies.

In vitro evaluation of the protective effects of Curcumin and Resveratrol against U87 Cells Induced by Beta-Amyloid

Objective: This study was carried out to investigate the effects of curcumin and resveratrol antioxidant enzymes in β-amyloid (Aβ)-induced in vitro Alzheimer's Disease (AD) cell model. Methods: In the study three groups were created; The control group consisted of U87 cell lines, the Aβ group in which the in vitro AH model was formed including the β-amyloid-induced U-87 cell lines, and the Aβ+ Curcumin+ Resveratrol group by adding curcumin and resveratrol to the Aβ group. Cell viability in groups was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test. Total Antioxidant Level (TAS), Superoxide dismutase (SOD), Total Oxidant Level (TOS) and Catalase (CAT) enzyme levels, results were analyzed to evaluate the antioxidant status. 
 Results: When cell viability was evaluated, it was determined that curcumin and resveratrol did not have cytotoxic effects. TAS levels were found to be statistically higher in the Aβ+ curcumin and resveratrol group compared to the Aβ group (p

A Network Pharmacology-Based Study on the Mechanism of Dibutyl Phthalate of Ocimum basilicum L. against Alzheimer's Disease through the AKT/GSK-3β Pathway.

Ocimum basilicum L. (OBL) is mainly used to treat neurological diseases in China. The preliminary work of this group showed that OBL improves cognitive impairment in Alzheimer's disease (AD). However, the underlying pharmacological mechanism remains unclear. The components of OBL were compiled by literature search, and their active ingredients were screened by online database. The drug targets of OBL in the treatment of AD were predicted and analyzed using information derived from sources such as the SwissTargetPrediction tool. And through the network visual analysis function of Cytoscape software and protein-protein interaction analysis (PPI), the core targets of OBL treatment of AD are predicted. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to analyze the related signaling pathways affected by OBL. Moreover, AutoDock software was used to assess the potential binding affinity between the core targets and the active compounds. Subsequently, in vivo experiment was conducted to verify the findings of network pharmacology. A total of 35 active compounds and 188 targets of OBL were screened, of which 43 common targets were related to AD. The active compounds of 35 OBLs induced 118 GO and 78 KEGG. The results of PPI and network topology parameter analysis show that targets such as MAPK1, GSK3B, NR3C2, ESR1, and EGFR are known as the core targets for the treatment of AD by OBL and are docked with the active ingredients of OBL. Molecular docking results suggest that diterbutyl phthalate (DBP) may be the main active component of OBL for the treatment of AD. Flow cytometry analysis results showed that apoptosis decreased with increasing DBP dose. In addition, DBP significantly decreased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) in the supernatant of Aβ 25-35-induced injury HT22 cell cultures, and it can be speculated that DBP has the ability to protect the stability of injured neuronal cells and improve the permeability of cell membranes, thus stabilizing the intracellular environment. Mechanistically, DBP may increase the mRNA levels of AKT, GSK-3β, etc. in AD cell models and regulate the phosphorylation of AKT/GSK-3β pathway-related. Conclusively, our study suggests that DBP, the main active component of OBL, has potential in the prevention or treatment of AD.

Inhibition of circ_0004381 improves cognitive function via miR-647/PSEN1 axis in an Alzheimer disease mouse model.

Circ_0004381 promotes neuronal damage in Parkinson disease, but its role in Alzheimer disease (AD) is unreported. The goal of this study was to investigate the role and potential mechanisms of circ_0004381 effects in AD models. Primary hippocampal neurons were treated with amyloid-β (Aβ1-42) to construct AD cell models. We found that circ_0004381 was upregulated in Aβ1-42-treated hippocampal neurons. Knockdown of circ_0004381 attenuated Aβ1-42-induced apoptosis, oxidative stress, and mitochondrial dysfunction in hippocampal neurons. Next, we induced microglia activation with lipopolysaccharide (LPS). The results of flow cytometry experiments showed that knockdown of circ_0004381 promoted microglial M2-type polarization and knockdown of circ_0004381 inhibited the production of inflammatory factors by microglia. Furthermore, knockdown of circ_0004381 improved cognitive function of male APPswe/PS1dE9 transgenic mice. Mechanistically, circ_0004381 regulated presenilin-1 (PSEN1) expression by absorbing miR-647. MiR-647 inhibition attenuated the effects of circ_0004381 knockdown. In conclusion, knockdown of circ_0004381 attenuated hippocampal neuronal damage and promoted microglia M2-type polarization through the miR-647/PSEN1 axis, ultimately improving cognitive function in AD model mice.

The Therapeutic Effects of Seven Lycopodium Compounds on Cell Models of Alzheimer's Disease.

As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD.

Transplantation of Nasal Olfactory Mucosa Mesenchymal Stem Cells Benefits Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disease that contributes to 60-70% of dementia in elderly people and is currently incurable. Current treatments only relieve the symptoms of AD and slow its progression. Achieving effective neural regeneration to ameliorate cognitive impairment is a major challenge in the treatment of AD. For the first time, we alleviated symptoms of AD in APPswe/PS1dE9 mice (hereafter referred to as AD mice) by transplantation of olfactory mucosa mesenchymal stem cells (OM-MSCs). Our study demonstrated that OM-MSC transplantation promotes amyloid-β (Aβ) clearance, downregulates the inflammatory response, and increases the M2/M1 ratio; OM-MSCs promote the conversion of BV2 (microglia) from M1 to M2 and also Aβ clearance in SH-SY5YAPPswe (AD cell model). OM-MSC-transplanted AD mice show improved cognitive learning and locomotive behavior. Our study suggests that OM-MSC transplantation could alleviate the symptoms of AD and promote Aβ clearance through immunomodulation, thus demonstrating the great potential and social value of OM-MSC treatment for AD patients.