Alzheimer’s disease(AD)has become an important public health issue worldwide.p-Coumaric acid(CA)and lactoferrin(Lf)possessed antioxidant,anti-inflammatory,and anti-AD activities.Herein,we hypothesized that a combinat...Alzheimer’s disease(AD)has become an important public health issue worldwide.p-Coumaric acid(CA)and lactoferrin(Lf)possessed antioxidant,anti-inflammatory,and anti-AD activities.Herein,we hypothesized that a combination treatment of CA and Lf would synergistically improve AD symptoms and studied its mechanisms.Twelve-week-old amyloid precursor protein(APP)/presenilin 1(PS1)mice were treated with CA,Lf,or both CA and Lf for 8 weeks.Results showed that individual and combined treatments could ameliorate cognitive deficits to varying degrees,with stronger effects for combined intervention than for CA or Lf alone.Specifically,combined treatment was most effective in improving nesting ability and reducing amyloidββ_(1-42)(Aβ_(1-42))deposition in mice.Moreover,combined treatment was more effective in suppressing APP,β-site APP cleavage enzyme 1,and inflammation;it inhibited the CCAAT-enhancer-binding protein(C/EBPβ)/asparagine endopeptidase(AEP)signaling pathway in the hippocampus and colon and upregulated the expression of tight junction protein zonula occludens-1 in the colon;it also decreased the Firmicutes/Bacteroidetes ratio at the phylum level and increased the relative abundance of Prevotellaceae,Lachnospira,and Eubacterium at the genus level.Overall,the combination of CA and Lf may ameliorate cognitive deficits in APP/PS1 mice by improving inflammation and inhibiting the C/EBPβ/AEP signaling pathway via modulating gut microbiome.展开更多
Proteolytic cleavage of tau by asparagine endopeptidase(AEP)creates tau-N368 fragments,which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer’s dis...Proteolytic cleavage of tau by asparagine endopeptidase(AEP)creates tau-N368 fragments,which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer’s disease patients.Nonetheless,the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear.Evidence suggests that signal transduction and activator of transcription-3(STAT3)is associated with modulating synaptic plasticity,cell apoptosis,and cognitive function.Using luciferase reporter assays,electrophoretic mobility shift assays,western blotting,and immunofluorescence,we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the nucleus.Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss,thereby improving the cognitive deficits in tau-N368 mice.Moreover,in tau-N368 mice,activation of STAT3 increased N-methyl-D-aspartic acid receptor levels,decreased Bcl-2 levels,reversed synaptic damage and neuronal loss,and thereby alleviated cognitive deficits caused by tau-N368.Taken together,STAT3 plays a critical role in truncated tau-related neuropathological changes.This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits.STAT3 can be used as a new molecular target to treat tau-N368-induced protein pathology.展开更多
Alzheimer’s disease(AD)is a complex neurodegenerative condition.5α-epoxyalantolactone(5α-EAL),a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla,has various pharmacological effects.This work...Alzheimer’s disease(AD)is a complex neurodegenerative condition.5α-epoxyalantolactone(5α-EAL),a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla,has various pharmacological effects.This work supposed to investigate the improved impact of 5α-EAL on cognitive impairment.5α-EAL inhibited the generation of nitric oxide(NO)in BV-2 cells stimulated with lipopolysaccharide(LPS)with an EC50 of 6.2μM.5α-EAL significantly reduced the production of prostaglandin E2(PGE2)and tumor necrosis factor-α(TNF-α),while also inhibiting the production of cyclooxygenase-2(COX-2)and inducible nitric oxide synthase(iNOS)proteins.The ability of 5α-EAL to penetrate the blood-brain barrier(BBB)was confirmed via a parallel artificial membrane permeation assay.Scopolamine(SCOP)-induced AD mice model was employed to assess the improved impacts of 5α-EAL on cognitive impairment in vivo.After the mice were pretreated with 5α-EAL(10 and 30 mg/kg per day,i.p.)for 21 days,the behavioral experiments indicated that the administration of the 5α-EAL could alleviate the cognitive and memory impairments.5α-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice.In summary,these findings highlight the beneficial effects of the natural product 5α-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.展开更多
Numerous studies have shown that many patients who suffer from type 2 diabetes mellitus exhibit cognitive dysfunction and neuronal synaptic impairments. Therefore, growing evidence suggests that type 2 diabetes mellit...Numerous studies have shown that many patients who suffer from type 2 diabetes mellitus exhibit cognitive dysfunction and neuronal synaptic impairments. Therefore, growing evidence suggests that type 2 diabetes mellitus has a close relationship with occurrence and progression of neurodegeneration and neural impairment in Alzheimer＇s disease. However, the relationship between metabolic disorders caused by type 2 diabetes mellitus and neurodegeneration and neural impairments in Alzheimer＇s disease is still not fully determined. Thus, in this study, we replicated a type 2 diabetic animal model by subcutaneous injection of newborn Sprague-Dawley rats with monosodium glutamate during the neonatal period. At 3 months old, the Barnes maze assay was performed to evaluate spatial memory function. Microelectrodes were used to measure electrophysiological function in the hippocampal CA1 region. Western blot assay was used to determine expression levels of glutamate ionotropic receptor NMDA type subunit 2 A（GluN2A） and GluN2B in the hippocampus. Enzyme-linked immunosorbent assay was used to determine levels of interleukin-1β, tumor necrosis factor α, and interleukin-6 in the hippocampus and cerebral cortex, as well as hippocampal amyloid beta（Aβ）1-40 and Aβ_（1-42） levels. Our results showed that in the rat model of type 2 diabetes mellitus caused by monosodium glutamate exposure during the neonatal period, latency was prolonged and the number of errors increased in the Barnes maze. Further, latency was increased and time in the escape platform quadrant shortened. Number of times crossing the platform was also reduced in the Morris water maze. After high frequency stimulation of the hippocampus, synaptic transmission was inhibited, expression of GluN2A and GluN2B were decreased in the hippocampus, expression of interleukin 1β, interleukin 6, and tumor necrosis factor α was increased in the hippocampus and cortex, and levels of Aβ_（1-40） and Aβ_（1-42） were increased in the hippocampus. These findings confirm that type 2 diabetes mellitus induced by neonatal monosodium glutamate exposure results in Alzheimer-like neuropathological changes and further causes cognitive deficits and neurodegeneration in young adulthood.展开更多
OBJECTIVE:To investigate effect of electroacupuncture(EA)with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8(SAMP8)mice and the related mechanisms.METHODS:8-month-old senescence-...OBJECTIVE:To investigate effect of electroacupuncture(EA)with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8(SAMP8)mice and the related mechanisms.METHODS:8-month-old senescence-accelerated-resistant(SAMR1)and SAMP8 mice were treated with EA at Baihui(GV 20),Shenshu(BL 23),and Taixi(KI 3)acupoint once a week for 8 weeks.The Morris water maze,enzyme linked immunosorbent assay,immunohistochemistry,and Western blot were used to assess Alzheimer’s disease(AD)-associated cognitive and neuroinflammatory phenotypes.RESULTS:Our data showed that EA treatment decreased activation of microglia and astrocytes,decreased levels of inflammatory factors including tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-17,and improved spatial memory deficits in SAMP8 mice.EA therapy with Bushen Jiannao exhibited anti-inflammatory properties and improved cognitive function.CONCLUSION:The present study indicates that EA treatment based on the interaction between kidney and brain can improve learning and memory ability by inhibiting activation of astrocytes and microglia and decreasing expression of pro-inflammatory cytokines,TNF-αand IL-17.EA treatment based on the interaction between kidney and brain may be an effective treatment for AD.展开更多
A moderate stress such as cold water swimming can raise the tolerance of the body to potentially injurious events. However, little is known about the mechanism of beneficial effects induced by moderate stress. In this...A moderate stress such as cold water swimming can raise the tolerance of the body to potentially injurious events. However, little is known about the mechanism of beneficial effects induced by moderate stress. In this study, we used a classic rat model of traumatic brain injury to test the hypothesis that cold water swimming preconditioning improved the recovery of cognitive functions and explored the mechanisms. Results showed that after traumatic brain injury, pre-conditioned rats（cold water swimming for 3 minutes at 4℃） spent a significantly higher percent of times in the goal quadrant of cold water swim, and escape latencies were shorter than for non-pretreated rats. The number of circulating endothelial progenitor cells was significantly higher in pre-conditioned rats than those without pretreatment at 0, 3, 6 and 24 hours after traumatic brain injury. Immunohistochemical staining and Von Willebrand factor staining demonstrated that the number of CD34~＋ stem cells and new blood vessels in the injured hippocampus tissue increased significantly in pre-conditioned rats. These data suggest that pretreatment with cold water swimming could promote the proliferation of endothelial progenitor cells and angiogenesis in the peripheral blood and hippocampus. It also ameliorated cognitive deficits caused by experimental traumatic brain injury.展开更多
Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular me...Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.展开更多
Background Schizophrenia is characterised by pervasive cognitive deficits that significantly impair daily functioning and quality of life.Pharmacological treatments have limited efficacy in addressing these deficits,h...Background Schizophrenia is characterised by pervasive cognitive deficits that significantly impair daily functioning and quality of life.Pharmacological treatments have limited efficacy in addressing these deficits,highlighting the need for adjunctive interventions like computerised cognitive training(CCT).Aims This study aimed to evaluate the effects of a 30-session CCT programme on mental well-being and cognitive performance in individuals with schizophrenia.Additionally,it assessed the usability and acceptability of CCT in this population.Methods A double-blind,randomised clinical trial was conducted with 54 participants assigned to intervention and control groups.Cognitive and mental health outcomes were assessed using validated tools such as the Depression Anxiety Stress Scale 21,the Warwick-Edinburgh Mental Wellbeing Scale and the Cambridge Neuropsychological Test Automated Battery.Usability was measured with the System Usability Scale(SUS).Assessments were conducted at baseline,post-intervention and 3 months post-follow-up.Results The CCT intervention significantly improved mental well-being,reduced stress and enhanced working memory(paired associate learning,spatial working memory and spatial span)compared with controls.However,no significant effects were observed for anxiety,depression or executive function.Usability scores were high(SUS=83.51),and compliance rates were strong(92.7%),indicating favourable participant engagement.Conclusion CCT demonstrated potential as an adjunctive treatment for schizophrenia,with significant improvements in targeted cognitive and mental health domains.The high usability and compliance rates support its feasibility for broader implementation.Further research is needed to optimise protocols and explore long-term benefits.CCT offers a promising approach to addressing mental health and cognitive challenges in schizophrenia,particularly for stress and working memory.Its usability and acceptability suggest it could be seamlessly integrated into clinical practice.展开更多
Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.Howeve...Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.展开更多
Objective To discuss the present status and progress of clinical research on the cognitive effects caused by different types of brain tumors and common treatments. Data sources The data used in this review were mainly...Objective To discuss the present status and progress of clinical research on the cognitive effects caused by different types of brain tumors and common treatments. Data sources The data used in this review were mainly from PubMed articles published in English from 1990 to Febuary 2012. Research terms were ＂cognitive deficits＂ or ＂cognitive dysfunction＂. Study selection Articals including any information about brain tumor related cognitive deficits were selected. Results It is widely accepted that brain tumors and related treatments can impair cognitive function across many domains, and can impact on patients＇ quality of life. Tumor localization, lateralization, surgery, drugs, radiotherapy and chemotherapy are all thought to be important factors in this process. However, some conflicting findings regarding brain tumor-related cognitive deficits have been reported. It can be difficult to determine the mechanism of these treatments, such as chemotherapy, antibiotics, antiepileptics, and steroids. Future research is needed to clarify these potential treatment effects. Conclusions Cognitive function is important for patients with brain tumor. Much more focus has been paid on this field. It should be regarded as an important prognostic index for the patients with brain tumor, and neuropsychological tests should be used in regular examinations.展开更多
Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This...Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
Background Major depressive disorder(MDD),characterised by persistent anhedonia and elevated suicide risk,represents a global mental health challenge.Recent studies suggest a link between gut-brain axis dysfunction an...Background Major depressive disorder(MDD),characterised by persistent anhedonia and elevated suicide risk,represents a global mental health challenge.Recent studies suggest a link between gut-brain axis dysfunction and depression.The natural compound paeoniflorin demonstrates clinically relevant antidepressant effects,yet its underlying neurobiological mechanisms remain elusive.Aims This study aims to examine how paeoniflorin alleviates depression-like behaviours in rats subjected to chronic unpredictable mild stress(CUMS)by modulating the function of gut-brain axis,and explore the connections between gut microbiota,metabolites and MDD.Methods Depression-like behaviours in rats were induced by CUMS,and the antidepressant effect of paeoniflorin was assessed using behavioural tests.The composition and function of the intestinal microbiota were analysed using 16S rRNA sequencing,and metabolomic analysis was performed on serum,hippocampus,jejunum and faecal samples.Enzyme-linked immunosorbent assay and hematoxylin and eosin staining were used to detect the levels of inflammatory factors and cortisol,as well as the infiltration of inflammatory cells in the jejunum of rats after cohousing.Long-term potentiation assays and Golgi staining were used to detect dendritic spine density and synaptic plasticity,respectively.Results Paeoniflorin significantly alleviated depression-like behaviours and cognitive deficits in CUMS rats.16S rRNA sequencing revealed that paeoniflorin improved the abundance and diversity of the gut microbiota in CUMS rats.Enrichment of differential metabolites in the brain,intestine,faeces and serum revealed a primary accumulation in the amino acid metabolism pathway.We further observed a correlation between the relative abundance of microbial communities and metabolites.Cohousing experiments verified that microbial metabolites of paeoniflorin can reduce neuroinflammation and improve synaptic plasticity.Conclusions Disruptions in gut microbiota and its metabolites impair gut-brain interactions.Paeoniflorin’s neuroprotective and antidepressant effects are mediated through the modulation of the function of the gut-brain axis.展开更多
Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we ...Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxietylike and depression-like behaviors induced by intraperitoneal injections of OXA(4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2 B subunit of N-methyl-Daspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg~(2+) in serum and cerebrospinal fluid(from ~0.8 mmol/L to ~ 0.6 mmol/L).The Mg~(2+) deficiency(0.6 mmol/L) upregulated tumor necrosis factor(TNF-α) and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-κB),and downregulated the NR2 B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-κB inhibitor,also prevented the OXAinduced memory/emotional deficits and the changes in TNF-α,p-p65,and microglia.Taken together,the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg~(2+) is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.展开更多
Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal scle rosis.There is no effective treatment for cognitive impairment.Medial septum cholinergic neurons have ...Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal scle rosis.There is no effective treatment for cognitive impairment.Medial septum cholinergic neurons have been reported to be a potential target for controlling epileptic seizures in tempo ral lobe epile psy.However,their role in the cognitive impairment of temporal lobe epilepsy remains unclear.In this study,we found that patients with temporal lobe epile psy with hippocampal sclerosis had a low memory quotient and severe impairment in verbal memory,but had no impairment in nonverbal memory.The cognitive impairment was slightly correlated with reduced medial septum volume and medial septum-hippocampus tra cts measured by diffusion tensor imaging.In a mouse model of chronic temporal lobe epilepsy induced by kainic acid,the number of medial septum choline rgic neurons was reduced and acetylcholine release was reduced in the hippocampus.Furthermore,selective apoptosis of medial septum cholinergic neurons mimicked the cognitive deficits in epileptic mice,and activation of medial septum cholinergic neurons enhanced hippocampal acetylcholine release and restored cognitive function in both kainic acid-and kindling-induced epile psy models.These res ults suggest that activation of medial septum cholinergic neurons reduces cognitive deficits in temporal lobe epilepsy by increasing acetylcholine release via projections to the hippocampus.展开更多
Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 m...Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four weeks.Behavioral tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by cladribine.On day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine release.Cryptotanshinone also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the hippocampus.Additionally,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the hippocampus.Conclusions:Cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.展开更多
Subclinical electroencephalogram discharges in children with psycho-cognitiVe problems are not uncommon. However, the clinical importance and relationship to cognitive deficits, as well as indications for medical trea...Subclinical electroencephalogram discharges in children with psycho-cognitiVe problems are not uncommon. However, the clinical importance and relationship to cognitive deficits, as well as indications for medical treatment, are not well understood. Transient cognitive impairment, which accompanies electroencephalogram discharges, could negatively influence cognitive abilities over time. Studies have suggested that treatment with antiepileptic drugs normalizes electroencephalogram results, thereby preventing electrical paroxysmal discharges that could be harmful to the developing brain. Physicians should attempt to differentiate between corresponding factors, such as subtle seizures, nature of underlying etiology, stable cognitive deficits, seizure-inducing effects, and potential side effects of antiepileptic drugs prior to initiation of medical treatment for definitive diagnosis of transient cognitive impairment and its consequences. Therefore appropriate criteria for patient selection and proper guidelines for medical therapy, should be addressed in future studies.展开更多
Background: Measuring cognition in clinical practice is clearly essential to the appropriate characterisation of patients’ clinical status and to the development of a personalised care plan. The Screen for Cognitive ...Background: Measuring cognition in clinical practice is clearly essential to the appropriate characterisation of patients’ clinical status and to the development of a personalised care plan. The Screen for Cognitive Impairment in Psychiatry (SCIP) has been developed in order to provide a brief and accessible tool allowing the evaluation of cognitive function in psychiatric conditions. Objective: We present a validation of a French version of the SCIP. Method: Translation from English into French is carried out using the accepted back-translation method. Seventy-two healthy volunteers are characterised by demographic questionnaires and a neuropsychological battery. The French version of the SCIP is then administered on two separate occasions separated by at least a one-week interval. Results: High internal consistencies as well as strong correlations with comparable neuropsychological tests are obtained. A normalised Cronbach’s α = 0.66 is obtained. Conclusions: The French version of the SCIP (SCIP-F) yields results comparable to the English version. The SCIP represents an essential tool for the preliminary evaluation of cognition. Its characteristics, brevity and the lack of need for a technological platform, allow for its integration into clinical practice. Further testing of SCIP-F in various psychiatric conditions will yield valuable information on its potential in clinical settings.展开更多
Attention deficit and hyperactivity disorder（ADHD） is a disorder characterized by behavioral symptoms including hyperactivity/impulsivity among children,adolescents,and adults.These ADHD related symptoms are influen...Attention deficit and hyperactivity disorder（ADHD） is a disorder characterized by behavioral symptoms including hyperactivity/impulsivity among children,adolescents,and adults.These ADHD related symptoms are influenced by the complex interaction of brain networks which were under explored.We explored age-related brain network differences between ADHD patients and typically developing（TD） subjects using resting state f MRI（rs-f MRI） for three age groups of children,adolescents,and adults.We collected rs-f MRI data from 184 individuals（27 ADHD children and 31 TD children;32 ADHD adolescents and 32 TD adolescents;and 31 ADHD adults and 31 TD adults）.The Brainnetome Atlas was used to define nodes in the network analysis.We compared three age groups of ADHD and TD subjects to identify the distinct regions that could explain age-related brain network differences based on degree centrality,a well-known measure of nodal centrality.The left middle temporal gyrus showed significant interaction effects between disease status（i.e.,ADHD or TD） and age（i.e.,child,adolescent,or adult）（P 0.001）.Additional regions were identified at a relaxed threshold（P 0.05）.Many of the identified regions（the left inferior frontal gyrus,the left middle temporal gyrus,and the left insular gyrus） were related to cognitive function.The results of our study suggest that aberrant development in cognitive brain regions might be associated with age-related brain network changes in ADHD patients.These findings contribute to better understand how brain function influences the symptoms of ADHD.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
基金funded by the National Natural Science Foundation of China(82103818)the Suzhou Applied Basic Research(Medical and Health)Science and Technology Innovation Project(SYW2024179)+1 种基金Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases,Soochow University(KJS2437)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Alzheimer’s disease(AD)has become an important public health issue worldwide.p-Coumaric acid(CA)and lactoferrin(Lf)possessed antioxidant,anti-inflammatory,and anti-AD activities.Herein,we hypothesized that a combination treatment of CA and Lf would synergistically improve AD symptoms and studied its mechanisms.Twelve-week-old amyloid precursor protein(APP)/presenilin 1(PS1)mice were treated with CA,Lf,or both CA and Lf for 8 weeks.Results showed that individual and combined treatments could ameliorate cognitive deficits to varying degrees,with stronger effects for combined intervention than for CA or Lf alone.Specifically,combined treatment was most effective in improving nesting ability and reducing amyloidββ_(1-42)(Aβ_(1-42))deposition in mice.Moreover,combined treatment was more effective in suppressing APP,β-site APP cleavage enzyme 1,and inflammation;it inhibited the CCAAT-enhancer-binding protein(C/EBPβ)/asparagine endopeptidase(AEP)signaling pathway in the hippocampus and colon and upregulated the expression of tight junction protein zonula occludens-1 in the colon;it also decreased the Firmicutes/Bacteroidetes ratio at the phylum level and increased the relative abundance of Prevotellaceae,Lachnospira,and Eubacterium at the genus level.Overall,the combination of CA and Lf may ameliorate cognitive deficits in APP/PS1 mice by improving inflammation and inhibiting the C/EBPβ/AEP signaling pathway via modulating gut microbiome.
基金supported in parts by the National Natural Science Foundation of China,Nos.82101501(to QF),and 82201589(to XH)。
文摘Proteolytic cleavage of tau by asparagine endopeptidase(AEP)creates tau-N368 fragments,which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer’s disease patients.Nonetheless,the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear.Evidence suggests that signal transduction and activator of transcription-3(STAT3)is associated with modulating synaptic plasticity,cell apoptosis,and cognitive function.Using luciferase reporter assays,electrophoretic mobility shift assays,western blotting,and immunofluorescence,we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the nucleus.Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss,thereby improving the cognitive deficits in tau-N368 mice.Moreover,in tau-N368 mice,activation of STAT3 increased N-methyl-D-aspartic acid receptor levels,decreased Bcl-2 levels,reversed synaptic damage and neuronal loss,and thereby alleviated cognitive deficits caused by tau-N368.Taken together,STAT3 plays a critical role in truncated tau-related neuropathological changes.This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits.STAT3 can be used as a new molecular target to treat tau-N368-induced protein pathology.
基金supported by the National Key Research and Development Program of China(No.2021YFE0103700)the National Natural Science Foundation of China(U21A20407,22274163,and 22374160)Shaanxi Fundamental Science Research Project for Chemistry and Biology(No.23JHQ054).
文摘Alzheimer’s disease(AD)is a complex neurodegenerative condition.5α-epoxyalantolactone(5α-EAL),a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla,has various pharmacological effects.This work supposed to investigate the improved impact of 5α-EAL on cognitive impairment.5α-EAL inhibited the generation of nitric oxide(NO)in BV-2 cells stimulated with lipopolysaccharide(LPS)with an EC50 of 6.2μM.5α-EAL significantly reduced the production of prostaglandin E2(PGE2)and tumor necrosis factor-α(TNF-α),while also inhibiting the production of cyclooxygenase-2(COX-2)and inducible nitric oxide synthase(iNOS)proteins.The ability of 5α-EAL to penetrate the blood-brain barrier(BBB)was confirmed via a parallel artificial membrane permeation assay.Scopolamine(SCOP)-induced AD mice model was employed to assess the improved impacts of 5α-EAL on cognitive impairment in vivo.After the mice were pretreated with 5α-EAL(10 and 30 mg/kg per day,i.p.)for 21 days,the behavioral experiments indicated that the administration of the 5α-EAL could alleviate the cognitive and memory impairments.5α-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice.In summary,these findings highlight the beneficial effects of the natural product 5α-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.
基金principally supported by the Initial Funding of PhD Research from Henan Medical College of China,No.1001/0106in parts by the Science and Technology Project of Henan Province of China,No.172102310105
文摘Numerous studies have shown that many patients who suffer from type 2 diabetes mellitus exhibit cognitive dysfunction and neuronal synaptic impairments. Therefore, growing evidence suggests that type 2 diabetes mellitus has a close relationship with occurrence and progression of neurodegeneration and neural impairment in Alzheimer＇s disease. However, the relationship between metabolic disorders caused by type 2 diabetes mellitus and neurodegeneration and neural impairments in Alzheimer＇s disease is still not fully determined. Thus, in this study, we replicated a type 2 diabetic animal model by subcutaneous injection of newborn Sprague-Dawley rats with monosodium glutamate during the neonatal period. At 3 months old, the Barnes maze assay was performed to evaluate spatial memory function. Microelectrodes were used to measure electrophysiological function in the hippocampal CA1 region. Western blot assay was used to determine expression levels of glutamate ionotropic receptor NMDA type subunit 2 A（GluN2A） and GluN2B in the hippocampus. Enzyme-linked immunosorbent assay was used to determine levels of interleukin-1β, tumor necrosis factor α, and interleukin-6 in the hippocampus and cerebral cortex, as well as hippocampal amyloid beta（Aβ）1-40 and Aβ_（1-42） levels. Our results showed that in the rat model of type 2 diabetes mellitus caused by monosodium glutamate exposure during the neonatal period, latency was prolonged and the number of errors increased in the Barnes maze. Further, latency was increased and time in the escape platform quadrant shortened. Number of times crossing the platform was also reduced in the Morris water maze. After high frequency stimulation of the hippocampus, synaptic transmission was inhibited, expression of GluN2A and GluN2B were decreased in the hippocampus, expression of interleukin 1β, interleukin 6, and tumor necrosis factor α was increased in the hippocampus and cortex, and levels of Aβ_（1-40） and Aβ_（1-42） were increased in the hippocampus. These findings confirm that type 2 diabetes mellitus induced by neonatal monosodium glutamate exposure results in Alzheimer-like neuropathological changes and further causes cognitive deficits and neurodegeneration in young adulthood.
基金Supported by National Key Research and Development Program—Research on Modernization of Traditional Chinese Medicine(Study on the Core Pathogenesis,Dialectical Elements and Syndrome Differentiation Standard of Kidney-Yang Deficiency Syndrome,No.2018YFC1704301)
文摘OBJECTIVE:To investigate effect of electroacupuncture(EA)with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8(SAMP8)mice and the related mechanisms.METHODS:8-month-old senescence-accelerated-resistant(SAMR1)and SAMP8 mice were treated with EA at Baihui(GV 20),Shenshu(BL 23),and Taixi(KI 3)acupoint once a week for 8 weeks.The Morris water maze,enzyme linked immunosorbent assay,immunohistochemistry,and Western blot were used to assess Alzheimer’s disease(AD)-associated cognitive and neuroinflammatory phenotypes.RESULTS:Our data showed that EA treatment decreased activation of microglia and astrocytes,decreased levels of inflammatory factors including tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-17,and improved spatial memory deficits in SAMP8 mice.EA therapy with Bushen Jiannao exhibited anti-inflammatory properties and improved cognitive function.CONCLUSION:The present study indicates that EA treatment based on the interaction between kidney and brain can improve learning and memory ability by inhibiting activation of astrocytes and microglia and decreasing expression of pro-inflammatory cytokines,TNF-αand IL-17.EA treatment based on the interaction between kidney and brain may be an effective treatment for AD.
基金supported by a grant from the Incubation Project of Natural Science Foundation of Tianjin Medical University General Hospital in China,No.303071901401the Natural Science Foundation of Tianjin of China,No.13JCZDJC30800the National Natural Science Foundation of China,No.81271361 and 81330029
文摘A moderate stress such as cold water swimming can raise the tolerance of the body to potentially injurious events. However, little is known about the mechanism of beneficial effects induced by moderate stress. In this study, we used a classic rat model of traumatic brain injury to test the hypothesis that cold water swimming preconditioning improved the recovery of cognitive functions and explored the mechanisms. Results showed that after traumatic brain injury, pre-conditioned rats（cold water swimming for 3 minutes at 4℃） spent a significantly higher percent of times in the goal quadrant of cold water swim, and escape latencies were shorter than for non-pretreated rats. The number of circulating endothelial progenitor cells was significantly higher in pre-conditioned rats than those without pretreatment at 0, 3, 6 and 24 hours after traumatic brain injury. Immunohistochemical staining and Von Willebrand factor staining demonstrated that the number of CD34~＋ stem cells and new blood vessels in the injured hippocampus tissue increased significantly in pre-conditioned rats. These data suggest that pretreatment with cold water swimming could promote the proliferation of endothelial progenitor cells and angiogenesis in the peripheral blood and hippocampus. It also ameliorated cognitive deficits caused by experimental traumatic brain injury.
基金supported by the National Natural Science Foundation of China, No. 81771140 (to YDZ)the Natural Science Foundation of Jiangsu Province of China, No. BK20201117 (to YDZ)Jiangsu “Six One Project” for Distinguished Medical Scholars of China, No. LGY2020013 (to TJ)
文摘Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.
基金supported by a grant from University of Social Welfare and Rehabilitation Sciences for the research expenses.
文摘Background Schizophrenia is characterised by pervasive cognitive deficits that significantly impair daily functioning and quality of life.Pharmacological treatments have limited efficacy in addressing these deficits,highlighting the need for adjunctive interventions like computerised cognitive training(CCT).Aims This study aimed to evaluate the effects of a 30-session CCT programme on mental well-being and cognitive performance in individuals with schizophrenia.Additionally,it assessed the usability and acceptability of CCT in this population.Methods A double-blind,randomised clinical trial was conducted with 54 participants assigned to intervention and control groups.Cognitive and mental health outcomes were assessed using validated tools such as the Depression Anxiety Stress Scale 21,the Warwick-Edinburgh Mental Wellbeing Scale and the Cambridge Neuropsychological Test Automated Battery.Usability was measured with the System Usability Scale(SUS).Assessments were conducted at baseline,post-intervention and 3 months post-follow-up.Results The CCT intervention significantly improved mental well-being,reduced stress and enhanced working memory(paired associate learning,spatial working memory and spatial span)compared with controls.However,no significant effects were observed for anxiety,depression or executive function.Usability scores were high(SUS=83.51),and compliance rates were strong(92.7%),indicating favourable participant engagement.Conclusion CCT demonstrated potential as an adjunctive treatment for schizophrenia,with significant improvements in targeted cognitive and mental health domains.The high usability and compliance rates support its feasibility for broader implementation.Further research is needed to optimise protocols and explore long-term benefits.CCT offers a promising approach to addressing mental health and cognitive challenges in schizophrenia,particularly for stress and working memory.Its usability and acceptability suggest it could be seamlessly integrated into clinical practice.
基金This work was supported by grants Beijing Natural Science Foundation(No.517100)National Key Research and Development Project(No.2017YFA0105200)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-2-006).
文摘Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.
文摘Objective To discuss the present status and progress of clinical research on the cognitive effects caused by different types of brain tumors and common treatments. Data sources The data used in this review were mainly from PubMed articles published in English from 1990 to Febuary 2012. Research terms were ＂cognitive deficits＂ or ＂cognitive dysfunction＂. Study selection Articals including any information about brain tumor related cognitive deficits were selected. Results It is widely accepted that brain tumors and related treatments can impair cognitive function across many domains, and can impact on patients＇ quality of life. Tumor localization, lateralization, surgery, drugs, radiotherapy and chemotherapy are all thought to be important factors in this process. However, some conflicting findings regarding brain tumor-related cognitive deficits have been reported. It can be difficult to determine the mechanism of these treatments, such as chemotherapy, antibiotics, antiepileptics, and steroids. Future research is needed to clarify these potential treatment effects. Conclusions Cognitive function is important for patients with brain tumor. Much more focus has been paid on this field. It should be regarded as an important prognostic index for the patients with brain tumor, and neuropsychological tests should be used in regular examinations.
基金supported by National Health Institute(NIH)grant NS099596(to LW and SPY),NS114221(to LW and SPY)Veterans Affair(VA)SPiRE grant RX003865(to SPY)+1 种基金supported by the O.Wayne Rollins Endowment Fund(to SPY)John E.Steinhaus Endowment Fund(to LW)。
文摘Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China(No 82305144)the Jiangsu Provincial Natural Science Foundation Project for Universities(No 23KJB360004)the National Natural Science Foundation Supporting Project of Nanjing University of Chinese Medicine(No XPT82305144).
文摘Background Major depressive disorder(MDD),characterised by persistent anhedonia and elevated suicide risk,represents a global mental health challenge.Recent studies suggest a link between gut-brain axis dysfunction and depression.The natural compound paeoniflorin demonstrates clinically relevant antidepressant effects,yet its underlying neurobiological mechanisms remain elusive.Aims This study aims to examine how paeoniflorin alleviates depression-like behaviours in rats subjected to chronic unpredictable mild stress(CUMS)by modulating the function of gut-brain axis,and explore the connections between gut microbiota,metabolites and MDD.Methods Depression-like behaviours in rats were induced by CUMS,and the antidepressant effect of paeoniflorin was assessed using behavioural tests.The composition and function of the intestinal microbiota were analysed using 16S rRNA sequencing,and metabolomic analysis was performed on serum,hippocampus,jejunum and faecal samples.Enzyme-linked immunosorbent assay and hematoxylin and eosin staining were used to detect the levels of inflammatory factors and cortisol,as well as the infiltration of inflammatory cells in the jejunum of rats after cohousing.Long-term potentiation assays and Golgi staining were used to detect dendritic spine density and synaptic plasticity,respectively.Results Paeoniflorin significantly alleviated depression-like behaviours and cognitive deficits in CUMS rats.16S rRNA sequencing revealed that paeoniflorin improved the abundance and diversity of the gut microbiota in CUMS rats.Enrichment of differential metabolites in the brain,intestine,faeces and serum revealed a primary accumulation in the amino acid metabolism pathway.We further observed a correlation between the relative abundance of microbial communities and metabolites.Cohousing experiments verified that microbial metabolites of paeoniflorin can reduce neuroinflammation and improve synaptic plasticity.Conclusions Disruptions in gut microbiota and its metabolites impair gut-brain interactions.Paeoniflorin’s neuroprotective and antidepressant effects are mediated through the modulation of the function of the gut-brain axis.
基金supported by the National Natural Science Foundation of China (31771166)。
文摘Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxietylike and depression-like behaviors induced by intraperitoneal injections of OXA(4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2 B subunit of N-methyl-Daspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg~(2+) in serum and cerebrospinal fluid(from ~0.8 mmol/L to ~ 0.6 mmol/L).The Mg~(2+) deficiency(0.6 mmol/L) upregulated tumor necrosis factor(TNF-α) and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-κB),and downregulated the NR2 B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-κB inhibitor,also prevented the OXAinduced memory/emotional deficits and the changes in TNF-α,p-p65,and microglia.Taken together,the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg~(2+) is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.
基金National Natural Science Foundation of China,Nos.82003 729 (to Ying W),82022071 (to YiW)Natural Science Foundation of Shandong Province of China,No.ZR2020QH357 (to Ying W)Public Welfare Technology Research Program of Zhejiang Province,No.LGF20H09001 1 (to JF)。
文摘Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal scle rosis.There is no effective treatment for cognitive impairment.Medial septum cholinergic neurons have been reported to be a potential target for controlling epileptic seizures in tempo ral lobe epile psy.However,their role in the cognitive impairment of temporal lobe epilepsy remains unclear.In this study,we found that patients with temporal lobe epile psy with hippocampal sclerosis had a low memory quotient and severe impairment in verbal memory,but had no impairment in nonverbal memory.The cognitive impairment was slightly correlated with reduced medial septum volume and medial septum-hippocampus tra cts measured by diffusion tensor imaging.In a mouse model of chronic temporal lobe epilepsy induced by kainic acid,the number of medial septum choline rgic neurons was reduced and acetylcholine release was reduced in the hippocampus.Furthermore,selective apoptosis of medial septum cholinergic neurons mimicked the cognitive deficits in epileptic mice,and activation of medial septum cholinergic neurons enhanced hippocampal acetylcholine release and restored cognitive function in both kainic acid-and kindling-induced epile psy models.These res ults suggest that activation of medial septum cholinergic neurons reduces cognitive deficits in temporal lobe epilepsy by increasing acetylcholine release via projections to the hippocampus.
基金funded by the Indian Council of Medical Research with Grant Number 2020-8817,New Delhi,India。
文摘Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four weeks.Behavioral tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by cladribine.On day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine release.Cryptotanshinone also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the hippocampus.Additionally,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the hippocampus.Conclusions:Cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.
文摘Subclinical electroencephalogram discharges in children with psycho-cognitiVe problems are not uncommon. However, the clinical importance and relationship to cognitive deficits, as well as indications for medical treatment, are not well understood. Transient cognitive impairment, which accompanies electroencephalogram discharges, could negatively influence cognitive abilities over time. Studies have suggested that treatment with antiepileptic drugs normalizes electroencephalogram results, thereby preventing electrical paroxysmal discharges that could be harmful to the developing brain. Physicians should attempt to differentiate between corresponding factors, such as subtle seizures, nature of underlying etiology, stable cognitive deficits, seizure-inducing effects, and potential side effects of antiepileptic drugs prior to initiation of medical treatment for definitive diagnosis of transient cognitive impairment and its consequences. Therefore appropriate criteria for patient selection and proper guidelines for medical therapy, should be addressed in future studies.
文摘Background: Measuring cognition in clinical practice is clearly essential to the appropriate characterisation of patients’ clinical status and to the development of a personalised care plan. The Screen for Cognitive Impairment in Psychiatry (SCIP) has been developed in order to provide a brief and accessible tool allowing the evaluation of cognitive function in psychiatric conditions. Objective: We present a validation of a French version of the SCIP. Method: Translation from English into French is carried out using the accepted back-translation method. Seventy-two healthy volunteers are characterised by demographic questionnaires and a neuropsychological battery. The French version of the SCIP is then administered on two separate occasions separated by at least a one-week interval. Results: High internal consistencies as well as strong correlations with comparable neuropsychological tests are obtained. A normalised Cronbach’s α = 0.66 is obtained. Conclusions: The French version of the SCIP (SCIP-F) yields results comparable to the English version. The SCIP represents an essential tool for the preliminary evaluation of cognition. Its characteristics, brevity and the lack of need for a technological platform, allow for its integration into clinical practice. Further testing of SCIP-F in various psychiatric conditions will yield valuable information on its potential in clinical settings.
基金supported by the Institute for Basic Science[grant No.IBS-R015-D1]the National Research Foundation of Korea(grant No.NRF-2016R1A2B4008545)
文摘Attention deficit and hyperactivity disorder（ADHD） is a disorder characterized by behavioral symptoms including hyperactivity/impulsivity among children,adolescents,and adults.These ADHD related symptoms are influenced by the complex interaction of brain networks which were under explored.We explored age-related brain network differences between ADHD patients and typically developing（TD） subjects using resting state f MRI（rs-f MRI） for three age groups of children,adolescents,and adults.We collected rs-f MRI data from 184 individuals（27 ADHD children and 31 TD children;32 ADHD adolescents and 32 TD adolescents;and 31 ADHD adults and 31 TD adults）.The Brainnetome Atlas was used to define nodes in the network analysis.We compared three age groups of ADHD and TD subjects to identify the distinct regions that could explain age-related brain network differences based on degree centrality,a well-known measure of nodal centrality.The left middle temporal gyrus showed significant interaction effects between disease status（i.e.,ADHD or TD） and age（i.e.,child,adolescent,or adult）（P 0.001）.Additional regions were identified at a relaxed threshold（P 0.05）.Many of the identified regions（the left inferior frontal gyrus,the left middle temporal gyrus,and the left insular gyrus） were related to cognitive function.The results of our study suggest that aberrant development in cognitive brain regions might be associated with age-related brain network changes in ADHD patients.These findings contribute to better understand how brain function influences the symptoms of ADHD.
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.
