[Objectives]Based on UPLC-Q-TOF-MS/MS,network pharmacology and molecular docking techniques,the mechanism of Euphorbia peplus in the treatment of Alzheimer s disease(AD)was studied.[Methods]The UPLC-Q-TOF-MS/MS techni...[Objectives]Based on UPLC-Q-TOF-MS/MS,network pharmacology and molecular docking techniques,the mechanism of Euphorbia peplus in the treatment of Alzheimer s disease(AD)was studied.[Methods]The UPLC-Q-TOF-MS/MS technique was used to rapidly analyze the chemical components of E.peplus.Active components and potential targets of E.peplus were retrieved from TCMSP and Swiss Target Prediction database,and AD targets were screened using GeneCards database.The targets of E.peplus in the treatment of AD were obtained.The PPI network was constructed using String platform,and the network topology of Cytoscape software was used to compute and screen key targets,and the GO and KEGG pathway enrichment analysis was carried out in Metascape database to construct the"component-target-pathway-disease"network.Molecular docking was used to predict the binding properties of active ingredients and targets.[Results]The results of UPLC-Q-TOF-MS/MS showed that 83 compounds were identified from E.peplus,including 19 terpenoids,10 phenolic acids and phenols,16 flavonoids,2 phenylpropanoids,4 coumarins,1 alkaloid,1 anthraquinone and 30 other compounds.The results of network pharmacological analysis showed that 82 active ingredients were screened,and 279 common targets were identified for the treatment of AD,among which the key targets were ALB(albumin),GAPDH(glyceraldehyde triphosphate dehydrogenase),TNF(tumor necrosis factor),AKT1(serine/threonine protein kinase 1),and IL6(interleukin-6).KEGG enrichment analysis showed that key signaling pathways include cancer pathways,lipid and atherosclerosis,Alzheimer s disease,insulin resistance,serotonergic synapses,calcium signaling pathway,cAMP signaling pathway and other signaling pathways.Molecular docking results showed that 14-deoxyandrographolide,dehydroandrographolide,licochalcone B,apigenin and naringenin may be the key components of E.peplus in the treatment of AD.[Conclusions]The results suggest that E.peplus can be used to treat Alzheimer s disease through multi-component,multi-target and multi-pathway.展开更多
[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,...[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,n=6)and human umbilical cord mesenchymal stem cell treatment group(MSC,n=6);six 6-month-old C57BL/6N mice were used as control group(CON,n=6).The mice in each group were treated with the fourth generation of human umbilical cord mesenchymal stem cells through tail vein.Four weeks later,the mice in each group were killed.The expression of GFP78 and ATF4 in the cortex of mice in each group was detected by Western blotting and real-time fluorescence quantitative PCR.[Results]The results of immunoblotting and real-time fluorescence quantitative PCR showed that the expression of GRP78 in MOD group was lower than that in CON group and the expression of ATF4 increased.The expression of GRP78 protein in MSC group was higher than that in MOD group,but the expression of ATF4 protein was lower.The results of real-time fluorescence quantitative PCR showed that the mRNA level of GRP78 decreased and the mRNA level of ATF4 increased in MOD group compared with CON group.The mRNA level of GRP78 in MSC group was higher than that in MOD group,while the mRNA level of ATF4 in MSC group was lower than that in MOD group.[Conclusions]Human umbilical cord mesenchymal stem cells can regulate the expression of GRP78/ATF4 pathway in APP/PSI mice,which may be related to the stress level of endoplasmic reticulum in the brain of APP/PS1 mice mediated by human umbilical cord mesenchymal stem cells.展开更多
Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport ...Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.展开更多
Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neur...Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.展开更多
Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hip...Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.展开更多
The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that...The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.展开更多
Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheime...Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.展开更多
Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypot...Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.展开更多
Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Hunting...Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated.In the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated.Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy.In addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo model.Moreover,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent.Most importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice.As revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.展开更多
The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centere...The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.展开更多
Alzheimer s disease,among the most common neurodegenerative disorders,is chara cterized by progressive cognitive impairment.At present,the Alzheimer’s disease main risk remains genetic ris ks,but major environmental ...Alzheimer s disease,among the most common neurodegenerative disorders,is chara cterized by progressive cognitive impairment.At present,the Alzheimer’s disease main risk remains genetic ris ks,but major environmental fa ctors are increasingly shown to impact Alzheimer’s disease development and progression.Microglia,the most important brain immune cells,play a central role in Alzheimer’s disease pathogenesis and are considered environmental and lifestyle"sensors."Factors like environmental pollution and modern lifestyles(e.g.,chronic stress,poor dietary habits,sleep,and circadian rhythm disorde rs)can cause neuroinflammato ry responses that lead to cognitive impairment via microglial functioning and phenotypic regulation.However,the specific mechanisms underlying interactions among these facto rs and microglia in Alzheimer’s disease are unclear.Herein,we:discuss the biological effects of air pollution,chronic stress,gut micro biota,sleep patterns,physical exercise,cigarette smoking,and caffeine consumption on microglia;consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer’s disease;and present the neuroprotective effects of a healthy lifestyle.Toward intervening and controlling these environmental risk fa ctors at an early Alzheimer’s disease stage,understanding the role of microglia in Alzheimer’s disease development,and to rgeting strategies to to rget microglia,co uld be essential to future Alzheimer’s disease treatments.展开更多
Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evoluti...Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.展开更多
Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheime...Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.展开更多
Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,di...Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,diet and physical activity are likely to affect the pathology of Alzheimer's disease as well as the gut microbiota.This demonstrates that it may be possible to prevent or halt the progression of Alzheimer's disease by regulating the gut microbiota using diet and physical activity strategies.Therefore,the present study reviews the association between these two interventions and gut microbiota in the human body.It also summarizes how these two interventions benefit Alzheimer's disease.Furthermore,the primary limitations of these two interventions are discussed and promising strategies are proposed,which may be beneficial to further study and develop the intervening measure for the progression of Alzheimer's disease.展开更多
The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease(AD),a neurodegenerative disease characterised by behavioural and cognitive impairment.However,most previous microbiome-based inte...The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease(AD),a neurodegenerative disease characterised by behavioural and cognitive impairment.However,most previous microbiome-based intervention studies have focused on single factors and yielded only modest cognitive improvements.Here,we proposed a multidomain intervention strategy that combined Bifidobacterium breve treatment with environmental enrichment(EE)training.In this study,we found that compared with EE or B.breve treatment alone,B.breve intervention combined with EE amplified its neuroprotective effects on AD mice,as reflected by improved cognition,inhibited neuroinflammation and enhanced synaptic function.Moreover,using microbiome and metabolome profiling,we found that the combination of B.breve and EE treatment restored AD-related gut microbiota dysbiosis and reversed microbial metabolite changes.Finally,by integrating behavioural and neurological data with metabolomic profiles,we revealed that the underlying mechanism may involve the modulation of microbiota-derived glutamine metabolism via gut-brain interactions.Collectively,combined B.breve intervention with EE treatment can alleviate AD-related cognitive impairment and improve brain function by regulating glutamine metabolism of the gut microbiome.Our findings provide a promising multidomain intervention strategy,with a combination of dietary microbiome-based and lifestyle-targeted interventions,to promote brain function and delay the progression of AD.展开更多
Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients w...Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients worldwide.The neuropathology of AD is perplexing and there is a scarcity of disease-modifying treatments.Currently,early diagnosis of AD has been made possible with the discovery of biological markers associated with pathology,providing strong support for the improvement of the disease status.The search for inhibitors of AD markers from dietary supplements(DSs)has become a major hot topic.Especially with the widespread use of DSs,DSs containing polyphenols,alkaloids,terpenes,polysaccharides and other bioactive components can prevent AD by reducing Aβdeposition,inhibiting tau protein hyperphosphorylation,reconstructing synaptic dysfunction,weakening cholinesterase activity,regulating mitochondrial oxidative stress,neuronal inflammation and apoptosis.This review summarizes the anti-AD effects of the main DSs and their bioactive constituents,as well as the potential molecular mechanisms covers from 2017 to 2023.Additionally,we discussed the opportunities and challenges faced by DSs in the process of AD prevention and treatment,aiming to further provide new perspectives for functional food development.展开更多
The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neur...The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research.展开更多
Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder.The subtle and insidious onset of its pathogenesis makes early detection of a formidable challenge in both contemporary neuroscience and clin...Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder.The subtle and insidious onset of its pathogenesis makes early detection of a formidable challenge in both contemporary neuroscience and clinical practice.In this study,we introduce an advanced diagnostic methodology rooted in theMed-3D transfermodel and enhanced with an attention mechanism.We aim to improve the precision of AD diagnosis and facilitate its early identification.Initially,we employ a spatial normalization technique to address challenges like clarity degradation and unsaturation,which are commonly observed in imaging datasets.Subsequently,an attention mechanism is incorporated to selectively focus on the salient features within the imaging data.Building upon this foundation,we present the novelMed-3D transfermodel,designed to further elucidate and amplify the intricate features associated withADpathogenesis.Our proposedmodel has demonstrated promising results,achieving a classification accuracy of 92%.To emphasize the robustness and practicality of our approach,we introduce an adaptive‘hot-updating’auxiliary diagnostic system.This system not only enables continuous model training and optimization but also provides a dynamic platform to meet the real-time diagnostic and therapeutic demands of AD.展开更多
BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social problems.The quality of life and prognosis of AD patients have attracted much attention.The role of chronic immune inflammation...BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social problems.The quality of life and prognosis of AD patients have attracted much attention.The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important.AIM To study the relationship among cognitive dysfunction,abnormal cellular immune function,neuroimaging results and poor prognostic factors in patients.METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020.Collect cognitive dysfunction performance characteristics,laboratory test data and neuroimaging data from medical records within 24 h of admission,including Mini Mental State Examination Scale score,drawing clock test,blood T lymphocyte subsets,and neutrophils and lymphocyte ratio(NLR),disturbance of consciousness,extrapyramidal symptoms,electroencephalogram(EEG)and head nucleus magnetic spectroscopy(MRS)and other data.Multivariate logistic regression analysis was used to determine independent prog-nostic factors.the modified Rankin scale(mRS)was used to determine whether the prognosis was good.The correlation between drug treatment and prognostic mRS score was tested by the rank sum test.RESULTS Univariate analysis showed that abnormal cellular immune function,extrapyramidal symptoms,obvious disturbance of consciousness,abnormal EEG,increased NLR,abnormal MRS,and complicated pneumonia were related to the poor prognosis of AD patients.Multivariate logistic regression analysis showed that the decrease in the proportion of T lym-phocytes in the blood after abnormal cellular immune function(odd ratio:2.078,95%confidence interval:1.156-3.986,P<0.05)was an independent risk factor for predicting the poor prognosis of AD.The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score(r=0.578,P<0.05).CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD.It is recommended that the proportion of T lymphocytes<55%is used as the cut-off threshold for predicting the poor prog-nosis of AD.The early and continuous drug treatment is associated with a good prognosis.展开更多
BACKGROUND Alzheimer’s disease(AD)is a neurodegenerative condition characterized by oxidative stress and neuroinflammation.Tanshinone ⅡA(Tan-ⅡA),a bioactive compound isolated from Salvia miltiorrhiza plants,has sho...BACKGROUND Alzheimer’s disease(AD)is a neurodegenerative condition characterized by oxidative stress and neuroinflammation.Tanshinone ⅡA(Tan-ⅡA),a bioactive compound isolated from Salvia miltiorrhiza plants,has shown potential neuroprotective effects;however,the mechanisms underlying such a function remain unclear.AIM To investigate potential Tan-ⅡA neuroprotective effects in AD and to elucidate their underlying mechanisms.METHODS Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology.To assess changes in oxidative stress and neuroinflammation,we performed enzyme-linked immunosorbent assay and western blotting.Additionally,the effect of Tan-ⅡA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Genetic changes related to the long non-coding RNA(lncRNA)nuclear-enriched abundant transcript 1(NEAT1)/microRNA(miRNA,miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.RESULTS In vivo,Tan-ⅡA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice.In vitro experiments showed that Tan-ⅡA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability,apoptosis,oxidative stress,and neuroinflammation.In this process,the lncRNA NEAT1-a potential therapeutic target-is highly expressed in AD mice and downregulated via Tan-ⅡA treatment.Mechanistically,NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p,which activates nuclear factor kappa-B(NF-κB)signaling,leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein,which exacerbates AD.Tan-ⅡA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.CONCLUSION This study demonstrates that Tan-ⅡA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway,serving as a foundation for the development of innovative approaches for AD therapy.展开更多
基金Supported by Science and Technology Fund of the Health Commission of Guizhou Province (gzwkj2021-440).
文摘[Objectives]Based on UPLC-Q-TOF-MS/MS,network pharmacology and molecular docking techniques,the mechanism of Euphorbia peplus in the treatment of Alzheimer s disease(AD)was studied.[Methods]The UPLC-Q-TOF-MS/MS technique was used to rapidly analyze the chemical components of E.peplus.Active components and potential targets of E.peplus were retrieved from TCMSP and Swiss Target Prediction database,and AD targets were screened using GeneCards database.The targets of E.peplus in the treatment of AD were obtained.The PPI network was constructed using String platform,and the network topology of Cytoscape software was used to compute and screen key targets,and the GO and KEGG pathway enrichment analysis was carried out in Metascape database to construct the"component-target-pathway-disease"network.Molecular docking was used to predict the binding properties of active ingredients and targets.[Results]The results of UPLC-Q-TOF-MS/MS showed that 83 compounds were identified from E.peplus,including 19 terpenoids,10 phenolic acids and phenols,16 flavonoids,2 phenylpropanoids,4 coumarins,1 alkaloid,1 anthraquinone and 30 other compounds.The results of network pharmacological analysis showed that 82 active ingredients were screened,and 279 common targets were identified for the treatment of AD,among which the key targets were ALB(albumin),GAPDH(glyceraldehyde triphosphate dehydrogenase),TNF(tumor necrosis factor),AKT1(serine/threonine protein kinase 1),and IL6(interleukin-6).KEGG enrichment analysis showed that key signaling pathways include cancer pathways,lipid and atherosclerosis,Alzheimer s disease,insulin resistance,serotonergic synapses,calcium signaling pathway,cAMP signaling pathway and other signaling pathways.Molecular docking results showed that 14-deoxyandrographolide,dehydroandrographolide,licochalcone B,apigenin and naringenin may be the key components of E.peplus in the treatment of AD.[Conclusions]The results suggest that E.peplus can be used to treat Alzheimer s disease through multi-component,multi-target and multi-pathway.
基金Supported by Major Project of Basic Scientific Research in Chengde Medical University(KY202217).
文摘[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,n=6)and human umbilical cord mesenchymal stem cell treatment group(MSC,n=6);six 6-month-old C57BL/6N mice were used as control group(CON,n=6).The mice in each group were treated with the fourth generation of human umbilical cord mesenchymal stem cells through tail vein.Four weeks later,the mice in each group were killed.The expression of GFP78 and ATF4 in the cortex of mice in each group was detected by Western blotting and real-time fluorescence quantitative PCR.[Results]The results of immunoblotting and real-time fluorescence quantitative PCR showed that the expression of GRP78 in MOD group was lower than that in CON group and the expression of ATF4 increased.The expression of GRP78 protein in MSC group was higher than that in MOD group,but the expression of ATF4 protein was lower.The results of real-time fluorescence quantitative PCR showed that the mRNA level of GRP78 decreased and the mRNA level of ATF4 increased in MOD group compared with CON group.The mRNA level of GRP78 in MSC group was higher than that in MOD group,while the mRNA level of ATF4 in MSC group was lower than that in MOD group.[Conclusions]Human umbilical cord mesenchymal stem cells can regulate the expression of GRP78/ATF4 pathway in APP/PSI mice,which may be related to the stress level of endoplasmic reticulum in the brain of APP/PS1 mice mediated by human umbilical cord mesenchymal stem cells.
基金supported by the Community Development Office of Hunan Provincial Science and Technology DepartmentChina,Nos.2020SK53613(to DH),21JJ31006(to DH)the Fundamental Research Funds of Central South University,Nos.CX20220375(to TX),2023zzts215(to MZ)。
文摘Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.
基金supported by the National Natural Science Foundation of China,No.82101493(to JY)。
文摘Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China,No.91849104(to YW)。
文摘Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.
基金supported by the Natural Science Foundation of Zhejiang Province of China,Nos.LQ22H090003(to JJ),LTGY23C090001(to XZ),LY23H020008(to BH)Sci-Tech Planning Project of Jiaxing,Nos.2021AY30001(to XZ)and 2022AY30020(to JJ).
文摘The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China,No.82074533(to LZ).
文摘Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.
文摘Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.
基金supported by FDCT grants from the Macao Science and Technology Development Fund,China,No.002/2023/ALC(to BYKL)Foshan Medicine Dengfeng Project of China 2019-2021(to BYKL)+3 种基金the Science and Technology Program of Sichuan Province,Nos.2022YFS0620(to DQ)and MZGC20230041(to XFW)the TCMs Commission of Sichuan Province,No.2021MS469(to YT)the Science and Technology Program of Luzhou,No.2022-WGR-194(to YT)the Southwest Medical University Science and Technology Program,No.2021NJXNYD04(to DQ).
文摘Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated.In the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated.Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy.In addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo model.Moreover,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent.Most importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice.As revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.
文摘The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.
基金supported by the National Natural Science Foundation of China,Nos.82071190 and 82371438(to LC)Innovative Strong School Project of Guangdong Medical University,No.4SG21230G(to LC)Scientific Research Foundation of Guangdong Medical University,No.GDMUM2020017(to CL)。
文摘Alzheimer s disease,among the most common neurodegenerative disorders,is chara cterized by progressive cognitive impairment.At present,the Alzheimer’s disease main risk remains genetic ris ks,but major environmental fa ctors are increasingly shown to impact Alzheimer’s disease development and progression.Microglia,the most important brain immune cells,play a central role in Alzheimer’s disease pathogenesis and are considered environmental and lifestyle"sensors."Factors like environmental pollution and modern lifestyles(e.g.,chronic stress,poor dietary habits,sleep,and circadian rhythm disorde rs)can cause neuroinflammato ry responses that lead to cognitive impairment via microglial functioning and phenotypic regulation.However,the specific mechanisms underlying interactions among these facto rs and microglia in Alzheimer’s disease are unclear.Herein,we:discuss the biological effects of air pollution,chronic stress,gut micro biota,sleep patterns,physical exercise,cigarette smoking,and caffeine consumption on microglia;consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer’s disease;and present the neuroprotective effects of a healthy lifestyle.Toward intervening and controlling these environmental risk fa ctors at an early Alzheimer’s disease stage,understanding the role of microglia in Alzheimer’s disease development,and to rgeting strategies to to rget microglia,co uld be essential to future Alzheimer’s disease treatments.
基金supported by the National Natural Science Foundation of China,No.81501106(to CF)Fund of Taishan Scholar Project(to CF)+1 种基金the Natural Science Foundation of Shandong Province,No.ZR2020QH106(to YH)the Medical and Health Science and Technology Development Plan of Shandong Province,No.202203010799(to QS)。
文摘Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China,Nos.82171194 and 81974155(both to JL)the Shanghai Municipal Science and Technology Commission Medical Guide Project,No.16411969200(to WZ)Shanghai Municipal Science and Technology Commission Biomedical Science and Technology Project,No.22S31902600(to JL)。
文摘Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.
基金financially supported by National Natural Science Foundation of China(32171035)the major fund project of Ningbo Science and Technology Bureau(2019B10034)+4 种基金Opened-end Fund of Key Laboratory(KFJJ-202101,ZPKLP202202)Public Project of Ningbo(202002N3167)Project of Yinzhou(2022AS025)Ningbo Rehabilitation Hospital(2022KY02)sponsored by a K.C.Wong Magna Fund in Ningbo University。
文摘Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,diet and physical activity are likely to affect the pathology of Alzheimer's disease as well as the gut microbiota.This demonstrates that it may be possible to prevent or halt the progression of Alzheimer's disease by regulating the gut microbiota using diet and physical activity strategies.Therefore,the present study reviews the association between these two interventions and gut microbiota in the human body.It also summarizes how these two interventions benefit Alzheimer's disease.Furthermore,the primary limitations of these two interventions are discussed and promising strategies are proposed,which may be beneficial to further study and develop the intervening measure for the progression of Alzheimer's disease.
基金supported by the National Natural Science Foundation of China(31972052,32021005,31820103010)the Fundamental Research Funds for the Central Universities(JUSRP22006,JUSRP51501)the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province。
文摘The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease(AD),a neurodegenerative disease characterised by behavioural and cognitive impairment.However,most previous microbiome-based intervention studies have focused on single factors and yielded only modest cognitive improvements.Here,we proposed a multidomain intervention strategy that combined Bifidobacterium breve treatment with environmental enrichment(EE)training.In this study,we found that compared with EE or B.breve treatment alone,B.breve intervention combined with EE amplified its neuroprotective effects on AD mice,as reflected by improved cognition,inhibited neuroinflammation and enhanced synaptic function.Moreover,using microbiome and metabolome profiling,we found that the combination of B.breve and EE treatment restored AD-related gut microbiota dysbiosis and reversed microbial metabolite changes.Finally,by integrating behavioural and neurological data with metabolomic profiles,we revealed that the underlying mechanism may involve the modulation of microbiota-derived glutamine metabolism via gut-brain interactions.Collectively,combined B.breve intervention with EE treatment can alleviate AD-related cognitive impairment and improve brain function by regulating glutamine metabolism of the gut microbiome.Our findings provide a promising multidomain intervention strategy,with a combination of dietary microbiome-based and lifestyle-targeted interventions,to promote brain function and delay the progression of AD.
基金financially supported by the National Key R&D Program of China(2022YFF1100301)Yunnan Revitalization Talents Support Plan-Young Talent Project(YNWRQNBJ-2018-357)。
文摘Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients worldwide.The neuropathology of AD is perplexing and there is a scarcity of disease-modifying treatments.Currently,early diagnosis of AD has been made possible with the discovery of biological markers associated with pathology,providing strong support for the improvement of the disease status.The search for inhibitors of AD markers from dietary supplements(DSs)has become a major hot topic.Especially with the widespread use of DSs,DSs containing polyphenols,alkaloids,terpenes,polysaccharides and other bioactive components can prevent AD by reducing Aβdeposition,inhibiting tau protein hyperphosphorylation,reconstructing synaptic dysfunction,weakening cholinesterase activity,regulating mitochondrial oxidative stress,neuronal inflammation and apoptosis.This review summarizes the anti-AD effects of the main DSs and their bioactive constituents,as well as the potential molecular mechanisms covers from 2017 to 2023.Additionally,we discussed the opportunities and challenges faced by DSs in the process of AD prevention and treatment,aiming to further provide new perspectives for functional food development.
基金supported by the Uehara Memorial Foundation,JSPS under the Joint Research Program implemented in association with SNSF(JRPs),Grant No.JPJSJRP20221507 and KAKENHI Grant No.22K15711,JST FOREST Program(Grant No.JPMJFR2269,Japan)2022 iPS Academia Japan Grant,Life Science Foundation of Japan,Kato Memorial Bioscience Foundation,THE YUKIHIKO MIYATA MEMORIAL TRUST FOR ALS RESEARCH,the ICHIRO KANEHARA FOUNDATION,Takeda Science Foundation,and the YAMAGUCHI UNIVERSITY FUNDATION(all to HN).
文摘The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research.
基金funded by the National Natural Science Foundation of China(No.62076044)Scientific Research Foundation of Chongqing University of Technology(No.2020ZDZ015).
文摘Alzheimer’s disease(AD)is a complex,progressive neurodegenerative disorder.The subtle and insidious onset of its pathogenesis makes early detection of a formidable challenge in both contemporary neuroscience and clinical practice.In this study,we introduce an advanced diagnostic methodology rooted in theMed-3D transfermodel and enhanced with an attention mechanism.We aim to improve the precision of AD diagnosis and facilitate its early identification.Initially,we employ a spatial normalization technique to address challenges like clarity degradation and unsaturation,which are commonly observed in imaging datasets.Subsequently,an attention mechanism is incorporated to selectively focus on the salient features within the imaging data.Building upon this foundation,we present the novelMed-3D transfermodel,designed to further elucidate and amplify the intricate features associated withADpathogenesis.Our proposedmodel has demonstrated promising results,achieving a classification accuracy of 92%.To emphasize the robustness and practicality of our approach,we introduce an adaptive‘hot-updating’auxiliary diagnostic system.This system not only enables continuous model training and optimization but also provides a dynamic platform to meet the real-time diagnostic and therapeutic demands of AD.
基金Supported by the National Natural Science Foundation of China,No.3206080019 and No.32060182Science and Technology Support Plan of Guizhou Province in China,No.[2020]4Y129Qiannan Prefecture Science and Technology Plan Project,No.[2022]01.
文摘BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social problems.The quality of life and prognosis of AD patients have attracted much attention.The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important.AIM To study the relationship among cognitive dysfunction,abnormal cellular immune function,neuroimaging results and poor prognostic factors in patients.METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020.Collect cognitive dysfunction performance characteristics,laboratory test data and neuroimaging data from medical records within 24 h of admission,including Mini Mental State Examination Scale score,drawing clock test,blood T lymphocyte subsets,and neutrophils and lymphocyte ratio(NLR),disturbance of consciousness,extrapyramidal symptoms,electroencephalogram(EEG)and head nucleus magnetic spectroscopy(MRS)and other data.Multivariate logistic regression analysis was used to determine independent prog-nostic factors.the modified Rankin scale(mRS)was used to determine whether the prognosis was good.The correlation between drug treatment and prognostic mRS score was tested by the rank sum test.RESULTS Univariate analysis showed that abnormal cellular immune function,extrapyramidal symptoms,obvious disturbance of consciousness,abnormal EEG,increased NLR,abnormal MRS,and complicated pneumonia were related to the poor prognosis of AD patients.Multivariate logistic regression analysis showed that the decrease in the proportion of T lym-phocytes in the blood after abnormal cellular immune function(odd ratio:2.078,95%confidence interval:1.156-3.986,P<0.05)was an independent risk factor for predicting the poor prognosis of AD.The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score(r=0.578,P<0.05).CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD.It is recommended that the proportion of T lymphocytes<55%is used as the cut-off threshold for predicting the poor prog-nosis of AD.The early and continuous drug treatment is associated with a good prognosis.
基金Supported by 2020 Guangxi Zhuang Autonomous Region Health Care Commission Self-Financing Research Projects,No.Z202000962023 Guangxi University Young and Middle-Aged Teachers’Basic Research Ability Improvement Project,No.2023KY0091+1 种基金National Natural Science Foundation of China,No.82260241the Natural Science Foundation of Guangxi Province,No.2015GXNSFAA139171 and No.2020GXNSFAA259053.
文摘BACKGROUND Alzheimer’s disease(AD)is a neurodegenerative condition characterized by oxidative stress and neuroinflammation.Tanshinone ⅡA(Tan-ⅡA),a bioactive compound isolated from Salvia miltiorrhiza plants,has shown potential neuroprotective effects;however,the mechanisms underlying such a function remain unclear.AIM To investigate potential Tan-ⅡA neuroprotective effects in AD and to elucidate their underlying mechanisms.METHODS Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology.To assess changes in oxidative stress and neuroinflammation,we performed enzyme-linked immunosorbent assay and western blotting.Additionally,the effect of Tan-ⅡA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Genetic changes related to the long non-coding RNA(lncRNA)nuclear-enriched abundant transcript 1(NEAT1)/microRNA(miRNA,miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.RESULTS In vivo,Tan-ⅡA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice.In vitro experiments showed that Tan-ⅡA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability,apoptosis,oxidative stress,and neuroinflammation.In this process,the lncRNA NEAT1-a potential therapeutic target-is highly expressed in AD mice and downregulated via Tan-ⅡA treatment.Mechanistically,NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p,which activates nuclear factor kappa-B(NF-κB)signaling,leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein,which exacerbates AD.Tan-ⅡA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.CONCLUSION This study demonstrates that Tan-ⅡA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway,serving as a foundation for the development of innovative approaches for AD therapy.
