Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,n...Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.展开更多
BACKGROUND New therapies are urgently needed for Alzheimer disease(AD). Sodium oligomannate(GV-971) is a marine-derived oligosaccharide that has been shown to decrease amyloid deposition, reduce neuroinflammation, rec...BACKGROUND New therapies are urgently needed for Alzheimer disease(AD). Sodium oligomannate(GV-971) is a marine-derived oligosaccharide that has been shown to decrease amyloid deposition, reduce neuroinflammation, reconstitute gut microbiota, and improve cognition in animal models of AD. A Phase 3 trial was conducted to assess efficacy and safety of GV-971. METHODS We conducted a Phase 3, double-blind placebo-controlled trial in patients with mild-to-moderate AD. Participants were randomized to receive placebo or GV-971(900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer′s Disease Assessment Scale(ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician′s Interview-Based Impression of Change(CIBIC+), Alzheimer′s Disease Cooperative Study-Activities of Daily Living(ADCS-ADL) scale, and Neuropsychiatric Inventory(NPI). The effect of GV-971 on the cerebral glucose metabolic rate was examined by 18 Fluorine-FDG PET in a subgroup. Safety and tolerability were monitored. RESULTS 818 participants were randomized, of which 408 were assigned to GV-971 and 410 to placebo. A significant drug-placebo difference in favor of GV-971 was present at each measurement time-point on the ADAS-Cog12. The difference between groups with regard to the change from baseline was-2.15 points(95% confidence interval,-3.07 to-1.23;P<0.0001;effect size 0.531) after 36 weeks treatment. There was a trend towards benefit on CIBIC+(P=0.0588) but not on the ADCS-ADL(P=0.5712), NPI(P=0.8004), or the CMRglu. TEAE incidence77% and 76%, comparable between the two groups. Two deaths occurred in the GV-971 group;these were determined not to be related to GV-971. CONCLUSION GV-971 demonstrated significant efficacy in improving cognition and showed sustained improvement across al observation periods. GV-971 was safe and well tolerated.展开更多
OBJECTIVE To investigate the protective effect of icariin(ICA) on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer disease mice(3×Tg-AD mice),and then to explore whether its mechanism is re...OBJECTIVE To investigate the protective effect of icariin(ICA) on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer disease mice(3×Tg-AD mice),and then to explore whether its mechanism is related to the improvement of brain glucose metabolism disorder.METHODS Three-month-old male 3 ×Tg-AD mice were randomly divided into three groups(n=10):3×Tg group,3×Tg+ICA low-dose group(30 mg·kg-1) and 3×Tg + ICA high-dose group(60 mg·kg-1).Age-matched male wild type(WT) mice were randomly divided into two groups(n=10):WT control group and WT+ICA60 mg·kg-1 group.ICA in vehicle(0.5% Tween-80 in distilled water) was given orally once a day for five months in the 3×Tg+ICA groups.3×Tg and WT control group were given an equal volume vehicle.Morris water maze was used to detect the learning and memory function of mice.Brain glucose metabolism in 3×Tg mice was observed by 18 F-FDG microPET imaging technique.Nissl staining and HE staining were used to evaluate the survival neurons in hippocampus of mice.Glucose oxidase assay was used to detect glucose contents in cortex of mice.The protein expression of APP,Aβ1-40,Aβ1-42 and glucose transporter 1(GLUT1),and the phosphorylation level of tau protein at multiple sites in hippocampus were detected by Western blotting.RESULTS Behavioral examination revealed a profound decrease learning and memory function,accompanied by a decrease in number of neuronal cells in 3×Tg-AD mice.Moreover,the cerebral18 F-FDG uptake rate per gram tissue was reduced and the glucose contents in the cortex were increased in 3×Tg-AD mice.In addition,Western blotting analysis showed that the expression of APP,Aβ1-40,Aβ1-42 proteins and the levels of tau protein phosphorylation at Ser199/202 and PHF-1(Ser396/404) sites were increased significantly,followed by a decrease of GLUT1 expression in hippocampus of 3×Tg-AD mice.All of these changes in behavioral functions,neuronal loss and related protein expression were reversed when mice were treated with ICA.CONCLUSION ICA can improve the learning and memory ability of AD model mice,the mechanism may be related to the improvement of cerebral glucose metabolism dysfunction by increasing the expression of GLUT1.展开更多
OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.S...OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In 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 treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,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 foun⁃dation 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.展开更多
Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and A...Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and AD.In recent years,studies related to resting-state functional MRI(rs-fMRI)indicated that the occurrence and development process of MCI and AD might be closely linked to spontaneous brain activity and alterations in functional connectivity among brain regions,and rs-fMRI could provide important reference for specific diagnosis and early treatment of MCI and AD.The research progresses of rs-fMRI for MCI and AD were reviewed in this article.展开更多
OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cogn...OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cognitive function and associated mechanisms.METHODS In present studies,we established the Alzheimer disease(AD)model by injecting Aβ25-35 into the lateral ventricle of rats.Then the spatial learning and memory abilities of LSS-treated rats were evaluated with the Morris water maze,meanwhile the protein expressions of AKT,GSK3β and Tau in the hippocampal neuron were analyzed by immunohistochemistry and Western blotting.RESULTS The results showed LSS can improve the cognitive functions of AD rats through shortening the escape latency,increasing the number across the platform,platform quadrant dwell time and the percentage of the total distance run platform quadrant.The protein expression of AKT was significantly up-regulated and that of GSK3β and Tau were decreased remarkably in the hippocampal CA1 area.CONCLUSION Our study is the first to show that LSS significantly improve the cognitive function and prevent hippocampal neuronal injury of the rats with AD by activation of the PI3K/AKT/GSK3βsignaling pathway,suggesting LSS may be developed into the nutrient supplement for the treatment of AD.展开更多
OBJECTIVE DL0410,one novel compound discovered inhigh throughput screening(HTS),was found to be a potent inhibitor for AChE and BuChE.Memory deficit mice model induced by scopolamine have been conducted to verify its ...OBJECTIVE DL0410,one novel compound discovered inhigh throughput screening(HTS),was found to be a potent inhibitor for AChE and BuChE.Memory deficit mice model induced by scopolamine have been conducted to verify its effects on the improvement of memory deficit.In this study,the effects of DL0410 on inhibitingβ-amyloid(Aβ)aggregation and attenuating cognition and memory impairment of APP/PS1 mice were further investigated.METHODS Th-T binding test was used to determinethe effect of DL0410 on Aβ1-42 aggregation.In addition,locomotor test,object recognition test,step-down test,and Morris Water maze were performedto investigate the effect of DL0410 on the cognition and memoryfunctions of APP/PS1 mice.RESULTS In vitro results showed that DL0410(10and 30μmol·L-1)could inhibit significantly the monomer Aβ1-42 from aggregation,when incubated together with monomer Aβ1-42 for 24h(P<0.01).Several behavioral tests demonstrated that DL0410(10and 30mg·kg-1)could shortened latency time innavigation test(P<0.01),increased platform crossing-times in space probe test(P<0.05),and reduced the error times in step-down test(P<0.01).CONCLUSIONDL0410 could inhibit Aβaggregation in vitro and alleviate cognition and memory impairment of APP/PS1 mice,which make DL0410 apromising candidate for Alzheimer′s disease treatment.展开更多
OBJECTIVE Transgenic mouse model has been widely used in pathogenesis study and preclinical drug evaluation in Alzheimer disease(AD).However,key differences are found between current animal models and clinical AD pati...OBJECTIVE Transgenic mouse model has been widely used in pathogenesis study and preclinical drug evaluation in Alzheimer disease(AD).However,key differences are found between current animal models and clinical AD patients regarding phenotypes.Lack of complete models that recapitulate broad spectrum of human AD neuropathology restricts efficacy of research projects and leads to frequent failure in AD drug development at clinical trial stages.This study aims to develop better mouse models of AD through modifying key phenotype insufficiency.METHODS By crossing different single and double transgenic mice with different mutations of APP/PS1 or tau and under prion,Thy1 or PDGF-β promoter,as well as selected knockout mice,I produced a dozen of bigenic models for neuropathology screening.Further neurochemical,behavioral and pharmacological validations were conducted in the optimized mouse model.RESULTS Neuropathology phenotyping found remarkable differences in tau pathology and neurodegeneration among individual APP/PS1/tau transgenic models.I had identified a triple mouse model named FADT that showed(1) huge mature tau pathology in hippocampus and cortex;(2) abundant tau truncation,as seen in human AD brain;(3)progressive neurodegeneration;(4)selective brain atrophy in hippocampus and entorhinal cortex;(5) reproducible and late onset spatial memory defects,etc.Importantly,remarkable tau pathology in this FADT model is mainly driven by beta-amyloid pathology,which differs from high expression of tau in rTg4510 model.CONCLUSION I had developed a new triple transgenic mouse model that recapitulates broad spectrum of human AD neuropathology features.This study will not only establish a solid model basis for AD pathophysiology investigation and drug development,but also reveal important clues on the interaction of beta-amyloid and tau pathologies in the brain.展开更多
The most common age-related neurodegenerative disease is Alzheimer disease(AD),the imbalance between Aβ generation and clearance accumulated in extracellular plaques(ECS). And aggregated hyperphosphorylated tau prote...The most common age-related neurodegenerative disease is Alzheimer disease(AD),the imbalance between Aβ generation and clearance accumulated in extracellular plaques(ECS). And aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. The sporadic form of AD is characterized by an overall impairment in Aβ clearance.(1) Immunotherapy for AD: Immunotherapy targeting Aβ clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aβ clearance. We found that oral vaccination with a recombinant AAV/Aβ vaccine increased the clearance of Aβ from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with r AAV/Aβ decreased the p62 level and up-regulated the LC3 B-Ⅱ/LC3 B-Ⅰ ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/m TOR pathway may account for autophagy enhancement. We also found increased anti-Aβ antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1 q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aβ clearance and modulating the autophagy pathway may be an important strategy for pre-clinical stage of AD(PCAD) prevention and intervention.(2)ECS in AD: Strategies that promote local growth of lymphatic vessels have the potential to improve clearance Aβ by meningeal lymphatics. whether enhancing clearance at the blood–brain barrier can improve lymphatic drainage function, remains to be addressed. Understanding substance transportation in brain ECS, especially in deep brain is essential for the complete answer to the question of how brain functions in the absence of a lymphatic drainage pathway. The brain interstitial fluid(ISF) drainage in deep brain was recently studied using a tracer-based MRI method, and a non-uniform ISF drainage was demonstrated with various distribution territories and movement speeds in different regions. In addition, Aβ deposition in the ECS and rescued memory in an APP/PS1 transgenic mouse of AD model,our findings are expected to have a potentially significant influence on brain-inspired and artificial intelligence, the future of which is very promising. Immunotherapy and local brain drug delivery via the brain ECS could circumvent the BBB and reduce systemic toxicity. Updated knowledge of the whole-brain ISF drainage system(ISS) provides a beneficial reference for improving the immunotherapeutic efficacy via ISS. New insights into how behave our and genetics modify ECS-ISS function should lead to the development of new preventive tools for PCAD and novel immunotherapy targeting Aβ clearance therapeutic targets.展开更多
OBJECTIVE To establish an in vitro cel model based on patient-specific human microglia to study the pathological mechanism of Alzheimer disease(AD) and to screen candidate drugs.METHODS First,the induced pluripotent s...OBJECTIVE To establish an in vitro cel model based on patient-specific human microglia to study the pathological mechanism of Alzheimer disease(AD) and to screen candidate drugs.METHODS First,the induced pluripotent stem cells(iPSCs) of AD patients and cognitive normal controls(CNC) were induced to hematopoietic progenitor cells(HPCs),and then HPCs were further induced with IL-34,M-CSF,GM-CSF and TGF-β1 for 20 d to obtain microglialike cells(MGLCs).HPCs were isolated by flow cytometry and MGLCs were identified by immunofluorescence.Cell phagocytosis was determined by phagocytosis neutral red experiusing Luminex assay kits,and the cell growth curve during the experiment was recorded by IncuCyte ZOOM.The phagocytic ability and secretion of cytokines of MGLCs were observed under the stimulation of LPS.RESULTS MGLCs from AD patients(AD-MGLCs) and CNC expressed microglia markers IBA1,TMEM119,P2 RY12,TREM2 and CD11 B.The results of phagocytosis neutral red experiment showed that under normal conditions,AD-MGLCs had stronger phagocytic ability(P<0.01).Stimulation by LPS resulted in increased phagocytosis of cel s,and the increase in phagocytosis of CNC-MGLCs was higher than AD-MGLCs(P<0.01).Experiments showed that high concentrations of LPS(>2 mg·L^(-1)) resulted in CNC-microglia death(P<0.01),whereas ADMGLCs did not show significant death.The cytokine assay showed that under normal conditions,the concentrations of IFN-γ and IL-2 secreted by AD patients were slightly higher than those of CNC.After LPS stimulation,the secretion of TNF-α,IL-6 and IL-10 was significantly increased.The increased secretion of AD-MGLCs was greater than that CNC-MGLCs(P<0.01).CONCLUSION AD-iPSCs derived MGLCs exhibit significant inflammatory characteristics and are more active than CNC,which may be associated with chronic inflammatory responses caused by microglia in AD,thus may provide valuable new tools to screen candidate drugs for the disease and to discover the mechanisms underlying AD pathogenesis.展开更多
Alzheimer disease(AD)is a common neurodegenerative disease in the elderly,but nowadays the pathogenesis of AD is unclear.Myeloid cell 2 trigger receptor(TREM2)is one of the most famous and most common rare mutations i...Alzheimer disease(AD)is a common neurodegenerative disease in the elderly,but nowadays the pathogenesis of AD is unclear.Myeloid cell 2 trigger receptor(TREM2)is one of the most famous and most common rare mutations in neurodegenerative disease research,and its functional site mutation can significantly increase the incidence of AD.In this paper,we summary the structure,localization,and function and related signaling pathways of TREM2,review the latest epidemiological findings of TREM2 associated with the pathogenesis of AD,and speculate on the possible role of TREM2 in the progression of this disease,as well as the expression of TREM2 and the role of soluble TREM2 in AD brain are further elucidated.Based on the potential protective effect of TREM2 in the pathogenesis of AD,Therefore,targeting TREM2 may provide new opportunities and a reference for AD treatment.As the TREM2 variant appears to be widely involved in neurodegenerative diseases,there is an urgent need to further study the function of TREM2 in the brain and to find its ligands involved in TREM2-mediated signaling transduction and its specific role in AD pathogenesis.展开更多
OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progressio...OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in amyloid precursor protein/presenilin 1(APP/PS1) transgenic mice. METHODS The upregulation of cerebral Klotho expression was mediated by intracerebroventricular administration of a lentiviral vector that encoded Klotho(LV-KL) in APP/PS1 transgenicmice.RESULTS LV-KL significantly increased Klotho overexpression and effectively ameliorated cognitive deficits and AD-like pathology in aged AD mice. LV-KL might induce autophagy activation and protein kinase B/mammalian target of rapamycin inhibition in both AD mice and cultured BV2 murine microglia. Meanwhile, LV-KL altered the expression of low density lipoprotein receptor-related protein 1(LRP-1), receptor for advanced glycation end products, P-glycoprotein and ABCA1 both at the brain microvascular and choroid plexus as well as the contents of plasma s LRP-1 in aged AD mice.CONCLUSION The current results indicate that Klotho plays a crucial role in the clearance of cerebral amyloid β protein and the progression of AD in mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.展开更多
OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key target...OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.展开更多
The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating rest...The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.展开更多
OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targ...OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7n ACh R,ACh E and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSION DL0410 is a promising candidate for further development for AD treatment.展开更多
OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated ...OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.展开更多
OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and iden...OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and identify the specific intestinal microbiota correlating with cognitive ability.METHODS Morris-water maze test,novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory.16S rRNA amplicon sequencing(Illumina,San Diego,CA,USA)was employed to investigate gut microbiota.RESULTS The treatment of LW-AFC improved cognitive impairments of SAMP8 mice,including spatial learning and memory ability,active avoidance response,and object recognition memory capability.Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units(OTUs)in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1(SAMR1) strains,the control of SAMP8 mice.The treatment of LW-AFC altered 22(16 increased and 6 decreased)OTUs in SAMP8 mice and among them,15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice.We further showed that there were7(3 negative and 4 positive correlation)OTUs significantly correlated with all the three types of cognitive abilities,at the order level,including Bacteroidales,Clostridiales,Desulfovibrionales,CW040,and two unclassified orders.LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice.CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.展开更多
Alzheimer disease(AD) is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy. Liuwei Dihuang decoction(LW),a classical traditional Ch...Alzheimer disease(AD) is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy. Liuwei Dihuang decoction(LW),a classical traditional Chinese medicine(TCM) formula,has long been used to treat various diseases,including dementia. A large number of pharmacological studies have showed that LW has beneficial effects on AD. LW-AFC is a new formula consisted of the main active components prepared fromLW.In this study,we found that administration of LW-AFC significantly improved behavioral performances in spontaneous locomotor activity,object recognition memory,spatial learning and memory,passive and active avoidance impairment in some AD mouse models,such as SAMP8 and APP/PS1 transgenic mice. Meanwhile,the impairments of long-term potentiation(LTP) were significantly ameliorated by LW-AFC administration in SAMP8 mice,as well as in corticosterone-induced LTP inhibition mice model.These effects were companied by alleviating of the neuron loss in the hippocampus,suppressing of A-beta deposition in the brain,and reducing of the concentration of Abeta42 in the hippocampus and plasma of APP/PS1 mice. The restoring and correcting of imbalance of hypothalamic-pituitary-adrenal(HPA) and hypothalamic-pituitary-gonadal(HPG) axis,the disorder of lymphocyte subsets,the abnormality of production of cytokine were also observed in LW-AFC treated SAMP8 and APP/PS1 mice.These findings indicated that LW-AFC ameliorated the behavioral and pathological deterioration of AD mice via the restoration of the NIM network in a holistic way,suggesting that LW-AFC might bea promising therapy for AD.展开更多
文摘Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.
文摘BACKGROUND New therapies are urgently needed for Alzheimer disease(AD). Sodium oligomannate(GV-971) is a marine-derived oligosaccharide that has been shown to decrease amyloid deposition, reduce neuroinflammation, reconstitute gut microbiota, and improve cognition in animal models of AD. A Phase 3 trial was conducted to assess efficacy and safety of GV-971. METHODS We conducted a Phase 3, double-blind placebo-controlled trial in patients with mild-to-moderate AD. Participants were randomized to receive placebo or GV-971(900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer′s Disease Assessment Scale(ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician′s Interview-Based Impression of Change(CIBIC+), Alzheimer′s Disease Cooperative Study-Activities of Daily Living(ADCS-ADL) scale, and Neuropsychiatric Inventory(NPI). The effect of GV-971 on the cerebral glucose metabolic rate was examined by 18 Fluorine-FDG PET in a subgroup. Safety and tolerability were monitored. RESULTS 818 participants were randomized, of which 408 were assigned to GV-971 and 410 to placebo. A significant drug-placebo difference in favor of GV-971 was present at each measurement time-point on the ADAS-Cog12. The difference between groups with regard to the change from baseline was-2.15 points(95% confidence interval,-3.07 to-1.23;P<0.0001;effect size 0.531) after 36 weeks treatment. There was a trend towards benefit on CIBIC+(P=0.0588) but not on the ADCS-ADL(P=0.5712), NPI(P=0.8004), or the CMRglu. TEAE incidence77% and 76%, comparable between the two groups. Two deaths occurred in the GV-971 group;these were determined not to be related to GV-971. CONCLUSION GV-971 demonstrated significant efficacy in improving cognition and showed sustained improvement across al observation periods. GV-971 was safe and well tolerated.
基金National Natural Science Foundation of China(81660599)Foundation of Zunyi Medical University (2013F-686+1 种基金2013F-738)Postgraduate Education Foundation of Guizhou Province(KYJJ2017008).
文摘OBJECTIVE To investigate the protective effect of icariin(ICA) on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer disease mice(3×Tg-AD mice),and then to explore whether its mechanism is related to the improvement of brain glucose metabolism disorder.METHODS Three-month-old male 3 ×Tg-AD mice were randomly divided into three groups(n=10):3×Tg group,3×Tg+ICA low-dose group(30 mg·kg-1) and 3×Tg + ICA high-dose group(60 mg·kg-1).Age-matched male wild type(WT) mice were randomly divided into two groups(n=10):WT control group and WT+ICA60 mg·kg-1 group.ICA in vehicle(0.5% Tween-80 in distilled water) was given orally once a day for five months in the 3×Tg+ICA groups.3×Tg and WT control group were given an equal volume vehicle.Morris water maze was used to detect the learning and memory function of mice.Brain glucose metabolism in 3×Tg mice was observed by 18 F-FDG microPET imaging technique.Nissl staining and HE staining were used to evaluate the survival neurons in hippocampus of mice.Glucose oxidase assay was used to detect glucose contents in cortex of mice.The protein expression of APP,Aβ1-40,Aβ1-42 and glucose transporter 1(GLUT1),and the phosphorylation level of tau protein at multiple sites in hippocampus were detected by Western blotting.RESULTS Behavioral examination revealed a profound decrease learning and memory function,accompanied by a decrease in number of neuronal cells in 3×Tg-AD mice.Moreover,the cerebral18 F-FDG uptake rate per gram tissue was reduced and the glucose contents in the cortex were increased in 3×Tg-AD mice.In addition,Western blotting analysis showed that the expression of APP,Aβ1-40,Aβ1-42 proteins and the levels of tau protein phosphorylation at Ser199/202 and PHF-1(Ser396/404) sites were increased significantly,followed by a decrease of GLUT1 expression in hippocampus of 3×Tg-AD mice.All of these changes in behavioral functions,neuronal loss and related protein expression were reversed when mice were treated with ICA.CONCLUSION ICA can improve the learning and memory ability of AD model mice,the mechanism may be related to the improvement of cerebral glucose metabolism dysfunction by increasing the expression of GLUT1.
基金Chinese Academy of Engi⁃neering Strategic Consulting Project(2022-XY-45)S&T Program of Hebei(22372502D)+1 种基金Scien⁃tific Research Project of Hebei Provincial Admin⁃istration of Traditional Chinese Medicine(023172)and Scientific Research Project of Hebei Provincial Administration of Traditional Chinese Medicine(2021273)。
文摘OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In 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 treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,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 foun⁃dation 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.
文摘Alzheimer's disease(AD)is a prevalent neurodegenerative disease characterized by cognitive decline in the early stage.Mild cognitive impairment(MCI)is considered as an intermediate stage between normal aging and AD.In recent years,studies related to resting-state functional MRI(rs-fMRI)indicated that the occurrence and development process of MCI and AD might be closely linked to spontaneous brain activity and alterations in functional connectivity among brain regions,and rs-fMRI could provide important reference for specific diagnosis and early treatment of MCI and AD.The research progresses of rs-fMRI for MCI and AD were reviewed in this article.
基金supported by Science and Technology Planning Project of Sichuan Province(2008SZ0050,14JC0798)Educational Commission of Sichuan Province(10ZA035,15ZA0155)+1 种基金Science and Technology Program of Luzhou(2015-S-43,2016LZXNYD-T03)Key Development Program of Southwest Medical University(2010ZD-010)
文摘OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cognitive function and associated mechanisms.METHODS In present studies,we established the Alzheimer disease(AD)model by injecting Aβ25-35 into the lateral ventricle of rats.Then the spatial learning and memory abilities of LSS-treated rats were evaluated with the Morris water maze,meanwhile the protein expressions of AKT,GSK3β and Tau in the hippocampal neuron were analyzed by immunohistochemistry and Western blotting.RESULTS The results showed LSS can improve the cognitive functions of AD rats through shortening the escape latency,increasing the number across the platform,platform quadrant dwell time and the percentage of the total distance run platform quadrant.The protein expression of AKT was significantly up-regulated and that of GSK3β and Tau were decreased remarkably in the hippocampal CA1 area.CONCLUSION Our study is the first to show that LSS significantly improve the cognitive function and prevent hippocampal neuronal injury of the rats with AD by activation of the PI3K/AKT/GSK3βsignaling pathway,suggesting LSS may be developed into the nutrient supplement for the treatment of AD.
基金The project supported by Ministry of Science and Technology 11th Five-Year Plan(2008ZX09401)
文摘OBJECTIVE DL0410,one novel compound discovered inhigh throughput screening(HTS),was found to be a potent inhibitor for AChE and BuChE.Memory deficit mice model induced by scopolamine have been conducted to verify its effects on the improvement of memory deficit.In this study,the effects of DL0410 on inhibitingβ-amyloid(Aβ)aggregation and attenuating cognition and memory impairment of APP/PS1 mice were further investigated.METHODS Th-T binding test was used to determinethe effect of DL0410 on Aβ1-42 aggregation.In addition,locomotor test,object recognition test,step-down test,and Morris Water maze were performedto investigate the effect of DL0410 on the cognition and memoryfunctions of APP/PS1 mice.RESULTS In vitro results showed that DL0410(10and 30μmol·L-1)could inhibit significantly the monomer Aβ1-42 from aggregation,when incubated together with monomer Aβ1-42 for 24h(P<0.01).Several behavioral tests demonstrated that DL0410(10and 30mg·kg-1)could shortened latency time innavigation test(P<0.01),increased platform crossing-times in space probe test(P<0.05),and reduced the error times in step-down test(P<0.01).CONCLUSIONDL0410 could inhibit Aβaggregation in vitro and alleviate cognition and memory impairment of APP/PS1 mice,which make DL0410 apromising candidate for Alzheimer′s disease treatment.
基金Science and Technology Development Fund of Shanghai Pudong New District (PKJ2017-Y37)Shanghai Natural Science Foundation(18ZR1417900).
文摘OBJECTIVE Transgenic mouse model has been widely used in pathogenesis study and preclinical drug evaluation in Alzheimer disease(AD).However,key differences are found between current animal models and clinical AD patients regarding phenotypes.Lack of complete models that recapitulate broad spectrum of human AD neuropathology restricts efficacy of research projects and leads to frequent failure in AD drug development at clinical trial stages.This study aims to develop better mouse models of AD through modifying key phenotype insufficiency.METHODS By crossing different single and double transgenic mice with different mutations of APP/PS1 or tau and under prion,Thy1 or PDGF-β promoter,as well as selected knockout mice,I produced a dozen of bigenic models for neuropathology screening.Further neurochemical,behavioral and pharmacological validations were conducted in the optimized mouse model.RESULTS Neuropathology phenotyping found remarkable differences in tau pathology and neurodegeneration among individual APP/PS1/tau transgenic models.I had identified a triple mouse model named FADT that showed(1) huge mature tau pathology in hippocampus and cortex;(2) abundant tau truncation,as seen in human AD brain;(3)progressive neurodegeneration;(4)selective brain atrophy in hippocampus and entorhinal cortex;(5) reproducible and late onset spatial memory defects,etc.Importantly,remarkable tau pathology in this FADT model is mainly driven by beta-amyloid pathology,which differs from high expression of tau in rTg4510 model.CONCLUSION I had developed a new triple transgenic mouse model that recapitulates broad spectrum of human AD neuropathology features.This study will not only establish a solid model basis for AD pathophysiology investigation and drug development,but also reveal important clues on the interaction of beta-amyloid and tau pathologies in the brain.
基金NBRD Program of China(2016YFC1306302 2016YFC1305903)+3 种基金National Natural Science Foundation of China(81571044 81471633 61450004 and 81171015)
文摘The most common age-related neurodegenerative disease is Alzheimer disease(AD),the imbalance between Aβ generation and clearance accumulated in extracellular plaques(ECS). And aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. The sporadic form of AD is characterized by an overall impairment in Aβ clearance.(1) Immunotherapy for AD: Immunotherapy targeting Aβ clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aβ clearance. We found that oral vaccination with a recombinant AAV/Aβ vaccine increased the clearance of Aβ from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with r AAV/Aβ decreased the p62 level and up-regulated the LC3 B-Ⅱ/LC3 B-Ⅰ ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/m TOR pathway may account for autophagy enhancement. We also found increased anti-Aβ antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1 q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aβ clearance and modulating the autophagy pathway may be an important strategy for pre-clinical stage of AD(PCAD) prevention and intervention.(2)ECS in AD: Strategies that promote local growth of lymphatic vessels have the potential to improve clearance Aβ by meningeal lymphatics. whether enhancing clearance at the blood–brain barrier can improve lymphatic drainage function, remains to be addressed. Understanding substance transportation in brain ECS, especially in deep brain is essential for the complete answer to the question of how brain functions in the absence of a lymphatic drainage pathway. The brain interstitial fluid(ISF) drainage in deep brain was recently studied using a tracer-based MRI method, and a non-uniform ISF drainage was demonstrated with various distribution territories and movement speeds in different regions. In addition, Aβ deposition in the ECS and rescued memory in an APP/PS1 transgenic mouse of AD model,our findings are expected to have a potentially significant influence on brain-inspired and artificial intelligence, the future of which is very promising. Immunotherapy and local brain drug delivery via the brain ECS could circumvent the BBB and reduce systemic toxicity. Updated knowledge of the whole-brain ISF drainage system(ISS) provides a beneficial reference for improving the immunotherapeutic efficacy via ISS. New insights into how behave our and genetics modify ECS-ISS function should lead to the development of new preventive tools for PCAD and novel immunotherapy targeting Aβ clearance therapeutic targets.
基金National Key Research and Development Program(2016YFC1306301).
文摘OBJECTIVE To establish an in vitro cel model based on patient-specific human microglia to study the pathological mechanism of Alzheimer disease(AD) and to screen candidate drugs.METHODS First,the induced pluripotent stem cells(iPSCs) of AD patients and cognitive normal controls(CNC) were induced to hematopoietic progenitor cells(HPCs),and then HPCs were further induced with IL-34,M-CSF,GM-CSF and TGF-β1 for 20 d to obtain microglialike cells(MGLCs).HPCs were isolated by flow cytometry and MGLCs were identified by immunofluorescence.Cell phagocytosis was determined by phagocytosis neutral red experiusing Luminex assay kits,and the cell growth curve during the experiment was recorded by IncuCyte ZOOM.The phagocytic ability and secretion of cytokines of MGLCs were observed under the stimulation of LPS.RESULTS MGLCs from AD patients(AD-MGLCs) and CNC expressed microglia markers IBA1,TMEM119,P2 RY12,TREM2 and CD11 B.The results of phagocytosis neutral red experiment showed that under normal conditions,AD-MGLCs had stronger phagocytic ability(P<0.01).Stimulation by LPS resulted in increased phagocytosis of cel s,and the increase in phagocytosis of CNC-MGLCs was higher than AD-MGLCs(P<0.01).Experiments showed that high concentrations of LPS(>2 mg·L^(-1)) resulted in CNC-microglia death(P<0.01),whereas ADMGLCs did not show significant death.The cytokine assay showed that under normal conditions,the concentrations of IFN-γ and IL-2 secreted by AD patients were slightly higher than those of CNC.After LPS stimulation,the secretion of TNF-α,IL-6 and IL-10 was significantly increased.The increased secretion of AD-MGLCs was greater than that CNC-MGLCs(P<0.01).CONCLUSION AD-iPSCs derived MGLCs exhibit significant inflammatory characteristics and are more active than CNC,which may be associated with chronic inflammatory responses caused by microglia in AD,thus may provide valuable new tools to screen candidate drugs for the disease and to discover the mechanisms underlying AD pathogenesis.
基金supported by National Natural Science Foundation of China(81473549)
文摘Alzheimer disease(AD)is a common neurodegenerative disease in the elderly,but nowadays the pathogenesis of AD is unclear.Myeloid cell 2 trigger receptor(TREM2)is one of the most famous and most common rare mutations in neurodegenerative disease research,and its functional site mutation can significantly increase the incidence of AD.In this paper,we summary the structure,localization,and function and related signaling pathways of TREM2,review the latest epidemiological findings of TREM2 associated with the pathogenesis of AD,and speculate on the possible role of TREM2 in the progression of this disease,as well as the expression of TREM2 and the role of soluble TREM2 in AD brain are further elucidated.Based on the potential protective effect of TREM2 in the pathogenesis of AD,Therefore,targeting TREM2 may provide new opportunities and a reference for AD treatment.As the TREM2 variant appears to be widely involved in neurodegenerative diseases,there is an urgent need to further study the function of TREM2 in the brain and to find its ligands involved in TREM2-mediated signaling transduction and its specific role in AD pathogenesis.
文摘OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in amyloid precursor protein/presenilin 1(APP/PS1) transgenic mice. METHODS The upregulation of cerebral Klotho expression was mediated by intracerebroventricular administration of a lentiviral vector that encoded Klotho(LV-KL) in APP/PS1 transgenicmice.RESULTS LV-KL significantly increased Klotho overexpression and effectively ameliorated cognitive deficits and AD-like pathology in aged AD mice. LV-KL might induce autophagy activation and protein kinase B/mammalian target of rapamycin inhibition in both AD mice and cultured BV2 murine microglia. Meanwhile, LV-KL altered the expression of low density lipoprotein receptor-related protein 1(LRP-1), receptor for advanced glycation end products, P-glycoprotein and ABCA1 both at the brain microvascular and choroid plexus as well as the contents of plasma s LRP-1 in aged AD mice.CONCLUSION The current results indicate that Klotho plays a crucial role in the clearance of cerebral amyloid β protein and the progression of AD in mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.
基金The project supported by the Research Special Fund for the National Great Science and Technology Projects(2012ZX09301002,2012ZX09508104,2013ZX09402203)the International Col aboration Project(2011DFR31240)Peking Union Medical College Graduate Student Innovation Fund(2013-1007-18)
文摘OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.
文摘The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.
基金supported by National Great Science and Technology Projects(2014ZX09507003-002,2013ZX09402203 and 2013ZX09508104001002)CAMS Initiative for Innovative Medicine(CAMS-I2M)(2016-I2M-3-007)National Natural Science Foundation of China(81673480)
文摘OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7n ACh R,ACh E and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSION DL0410 is a promising candidate for further development for AD treatment.
基金The project supported by the National Training Program of Innovation and Entrepreneurship for Undergraduates(201610439108)
文摘OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.
基金supported by National Science and Technology Major Project(2013ZX09508104,2012ZX09301003-002-001)
文摘OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and identify the specific intestinal microbiota correlating with cognitive ability.METHODS Morris-water maze test,novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory.16S rRNA amplicon sequencing(Illumina,San Diego,CA,USA)was employed to investigate gut microbiota.RESULTS The treatment of LW-AFC improved cognitive impairments of SAMP8 mice,including spatial learning and memory ability,active avoidance response,and object recognition memory capability.Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units(OTUs)in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1(SAMR1) strains,the control of SAMP8 mice.The treatment of LW-AFC altered 22(16 increased and 6 decreased)OTUs in SAMP8 mice and among them,15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice.We further showed that there were7(3 negative and 4 positive correlation)OTUs significantly correlated with all the three types of cognitive abilities,at the order level,including Bacteroidales,Clostridiales,Desulfovibrionales,CW040,and two unclassified orders.LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice.CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.
文摘Alzheimer disease(AD) is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy. Liuwei Dihuang decoction(LW),a classical traditional Chinese medicine(TCM) formula,has long been used to treat various diseases,including dementia. A large number of pharmacological studies have showed that LW has beneficial effects on AD. LW-AFC is a new formula consisted of the main active components prepared fromLW.In this study,we found that administration of LW-AFC significantly improved behavioral performances in spontaneous locomotor activity,object recognition memory,spatial learning and memory,passive and active avoidance impairment in some AD mouse models,such as SAMP8 and APP/PS1 transgenic mice. Meanwhile,the impairments of long-term potentiation(LTP) were significantly ameliorated by LW-AFC administration in SAMP8 mice,as well as in corticosterone-induced LTP inhibition mice model.These effects were companied by alleviating of the neuron loss in the hippocampus,suppressing of A-beta deposition in the brain,and reducing of the concentration of Abeta42 in the hippocampus and plasma of APP/PS1 mice. The restoring and correcting of imbalance of hypothalamic-pituitary-adrenal(HPA) and hypothalamic-pituitary-gonadal(HPG) axis,the disorder of lymphocyte subsets,the abnormality of production of cytokine were also observed in LW-AFC treated SAMP8 and APP/PS1 mice.These findings indicated that LW-AFC ameliorated the behavioral and pathological deterioration of AD mice via the restoration of the NIM network in a holistic way,suggesting that LW-AFC might bea promising therapy for AD.
