During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Agin...During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Aging is one of the main risk factors for the development of neurodegenerative diseases,such as Alzheimer’s disease.One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates.The most studied brain aggregates are the senile plaques,formed by Aβpeptide;however,the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity.It is reported that neurons undergo severe mitochondrial dysfunction with age,with a decrease in adenosine 5′-triphosphate production,loss of the mitochondrial membrane potential,redox imbalance,impaired mitophagy,and loss of calcium buffer capacity.Interestingly,abnormal tau protein interacts with several mitochondrial proteins,suggesting that it could induce mitochondrial dysfunction.Nevertheless,whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown.A recent study of our laboratory shows that phosphorylated tau at Ser396/404(known as PHF-1),an epitope commonly related to pathology,accumulates inside mitochondria during normal aging.This accumulation occurs preferentially in synaptic mitochondria,which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals.Here,we review the main tau modifications promoting mitochondrial dysfunction,and the possible mechanism involved.Also,we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging.Finally,we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease,which could be considered as an early event in the neurodegenerative process.Thus,phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.展开更多
A lack of convenient and reliable biomarkers for diagnosis and prognosis is a common challenge for neurodegenerative diseases such as Alzheimer's disease(AD).Recent advancement in ultrasensitive protein assays has...A lack of convenient and reliable biomarkers for diagnosis and prognosis is a common challenge for neurodegenerative diseases such as Alzheimer's disease(AD).Recent advancement in ultrasensitive protein assays has allowed the quantification of tau and phosphorylated tau proteins in peripheral plasma.Here we identified 66 eligible studies reporting quantification of plasma tau and phosphorylated tau 181(ptau181)using four ultrasensitive methods.Meta-analysis of these studies confirmed that the AD patients had significantly higher plasma tau and ptau181 levels compared with controls,and that the plasma tau and ptau181 could predict AD with high-accuracy area under curve of the Receiver Operating Characteristic Therefore,plasma tau and plasma ptau181 can be considered as biomarkers for AD diagnosis.展开更多
Type 1 diabetes mellitus(T1DM)-induced cognitive dysfunction is common,but its underlying mechanisms are still poorly understood.In this study,we found that knockout of conventional protein kinase C(cPKC)γsignificant...Type 1 diabetes mellitus(T1DM)-induced cognitive dysfunction is common,but its underlying mechanisms are still poorly understood.In this study,we found that knockout of conventional protein kinase C(cPKC)γsignificantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles,but did not affect the activities of GSK-3βand PP2A in the hippocampal neurons of T1DM mice.cPKCγdeficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice.Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγdeficiency in T1DM mice.Moreover,cPKCγdeficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro.The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor.In conclusion,these results indicated that cPKCγpromotes autophagy through the AMPK/mTOR signaling pathway,thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.展开更多
Background:Tau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy,suggesting that therapies which increase anti-tau antibodies ...Background:Tau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy,suggesting that therapies which increase anti-tau antibodies might slow the development and/or progression of Alzheimer’s disease(AD).The extent to which individuals with no cognitive impairment(NCI)possess serum anti-tau antibodies,and whether their concentrations of these antibodies differ from anti-tau antibody levels in persons with mild cognitive impairment(MCI)or AD,are unclear.Previous studies measuring these antibodies did not account for antibody polyvalent binding,which can be extensive,nor that antibody binding to phosphorylated tau peptides could be due to binding to non-phosphorylated epitopes on those peptides.Methods:An ELISA controlling for these factors was used to measure the specific binding of serum IgG and IgM to phosphorylated(“pTau;”phosphorylated at Serine-199 and Serine-202)and non-phosphorylated(“non-pTau”)tau 196-207 in subjects with NCI,MCI,or AD(n=10/group).Between-group differences in these antibody levels were evaluated for statistical significance,and correlations were examined in pooled data from all subjects between these antibody levels and subject age,global cognitive functioning,and NFT counts.Results:Specific IgG binding to pTau and non-pTau was detected in all subjects except for one NCI control.Specific IgM binding was detected to pTau in all subjects except for two AD patients,and to non-pTau in all subjects.Mean pTau IgG was increased in MCI subjects by 53% and 70% vs.AD and NCI subjects respectively(both p<0.05),while no significant differences were found between groups for non-pTau IgG(p=0.052),pTau IgM,or non-pTau IgM.Non-pTau IgG was negatively associated with global cognition(Spearman rho=−0.50).Conclusions:Specific binding of serum IgG and IgM to phosphorylated and non-phosphorylated tau may be present in older persons regardless of their cognitive status.Serum IgG to phosphorylated tau may be increased in individuals with MCI,but this unexpected finding requires confirmation.The approach used in this study to measure specific serum antibodies to phosphorylated tau should be useful for measuring antibodies to other post-translationally-modified proteins that are of relevance to neurodegenerative disorders.展开更多
Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the...Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.展开更多
Tau,a primary component of microtubule-associated protein,promotes microtubule assembly and/or disassembly and maintains the stability of the microtubule structure.Although the importance of tau in neurodegenerative d...Tau,a primary component of microtubule-associated protein,promotes microtubule assembly and/or disassembly and maintains the stability of the microtubule structure.Although the importance of tau in neurodegenerative diseases has been well demonstrated,whether tau is involved in peripheral nerve regeneration remains unknown.In the current study,we obtained sciatic nerve tissue from adult rats 0,1,4,7,and 14 days after sciatic nerve crush and examined tau m RNA and protein expression levels and the location of tau in the sciatic nerve following peripheral nerve injury.The results from our quantitative reverse transcription polymerase chain reaction analysis showed that compared with the uninjured control sciatic nerve,m RNA expression levels for both tau and tau tubulin kinase 1,a serine/threonine kinase that regulates tau phosphorylation,were decreased following peripheral nerve injury.Our western blot assay results suggested that the protein expression levels of tau and phosphorylated tau initially decreased 1 day post nerve injury but then gradually increased.The results of our immunohistochemical labeling showed that the location of tau protein was not altered by nerve injury.Thus,these results showed that the expression of tau was changed following sciatic nerve crush,suggesting that tau may be involved in peripheral nerve repair and regeneration.展开更多
[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was rep...[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was replicated by injection of Aβ_(25-35) in the left lateral ventricles of SD rats. The low dose( 25 mg/kg),middle dose( 50 mg/kg) and high dose( 100 mg/kg) notoginsenoside Rg1 was used for intragastric administration,respectively,two times every day. After 4 weeks,the Morris water maze test was done to detect the learning and memory capacity,and the immunoblotting,immunohistochemical methods were used to detect the changes in the phosphorylation level and distribution of tau protein in hippocampus of the rats. [Results] After the intracerebroventricular injection of Aβ_(25-35),the learning and memory capacity of the model rats was significantly lower than the learning and memory capacity of the normal control rats. The immunoblotting test results showed that the phosphorylation level of tau protein threonine 231 site( Thr231) in hippocampus was significantly increased,and the nonphosphorylation level was significantly decreased. The morphological testing results showed that the phosphorylation level of tau protein Thr231 of AD model rats was increased markedly in region of DG,CA1 and CA3 of the hippocampus. The intervention of the middle dose notoginsenoside Rg1 could significantly improve the learning and memory capacity of the model rats in Morris water maze. The notoginsenoside Rg1 in three different doses could all reduce the phosphorylation level of tau protein Thr231 in the hippocampal DG,CA1,CA3 regions,and there were no significant differences among the three doses. [Conclusions]The notoginsenoside Rg1 could improve Aβ_(25-35)-induced spatial learning and memory impairment of the AD model rats,and decreased the phosphorylation level of tau protein in hippocampus.展开更多
Helicobacter pylori(H.pylori) infection is a recognized risk factor of dementia, while its role and mechanism in Alzheimer disease(AD) remained unclarified. Our previous study has identified that injection of soluble ...Helicobacter pylori(H.pylori) infection is a recognized risk factor of dementia, while its role and mechanism in Alzheimer disease(AD) remained unclarified. Our previous study has identified that injection of soluble H.pylori filtrate could induce AD-like pathologic changes and cognitive impairment in SD rats. In the present study, we further explored the effect of long-term stomach colonization of H.pylori bacteria on the brains of SD rats. The results showed that H.pylori bacteria gavage induced an efficient colonization of H.pylori in the stomach after four weeks. However, there was no significant change of tau phosphorylation at Thr205(pT205), Thr231(pT231), Ser396(pS396) and Ser404(pS404) sites in the hippocampus and cerebral cortex. The H.pylori-infected rats also showed no cognitive impairment. These observations may result from inefficient release of bacterial pathogenic factors or the overall lack of host inflammatory responses. We conclude that SD rat with long-term H.pylori colonization in the stomach is not a suitable animal model for exploring the effects of H.pylori infection on brain function in human beings; administration of bacterial filtrates may better reveal the systemic pathologic changes induced by bacterial infection in animals which show a negative host response to bacterial colonization.展开更多
Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease(AD).However,there are currently no effective drugs that can target chronic stress to prevent AD.In this study,we explored the ne...Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease(AD).However,there are currently no effective drugs that can target chronic stress to prevent AD.In this study,we explored the neuroprotective effect of hydroxysafflor yellow A(HSYA)against chronic mild stress(CMS)-induced memory impairments in mice and the underlying mechanism.The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice.HSYA increased the expression of brain-derived neurotrophic factor(BDNF)and activated downstream tropomyosin-related kinase B(TrkB)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling.HSYA decreased the expression of regulator of calcineurin 1-1L(RCAN1-1L)that could promote the activity of glycogen synthase kinase-3β(GSK-3β).HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3βand cyclin-dependent kinase-5(Cdk5).Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation,tau phosphorylation and memory impairments.HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.展开更多
rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal h...rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal hyperactivity behavior.Cornel iridoid glycoside(CIG)is an active ingredient extracted from Cornus officinalis,a traditional Chinese herb.The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity,and related mechanisms.The emotional hyperactivity was detected by locomotor activity test and Y maze test.Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau.Western blotting was used to detect the expression of related proteins.The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype,prevented neuronal loss,reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice.Meanwhile,CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors(NMDARs)subunits GluN1 and GluN2A andαamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunits GluA1 and GluA2,and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase IIα(p-CaMK IIα)in the brain of rTg4510 mice.In conclusion,CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.展开更多
Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of sid...Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of side effects.Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD.Hypoxia is one of the important factors that contribute to the pathogenesis of AD.Multiple cellular processes synergistically promote hypoxia,including aging,hypertension,diabetes,hypoxia/obstructive sleep apnea,obesity,and traumatic brain injury.Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD,such as amyloid-beta metabolism,tau phosphorylation,autophagy,neuroinflammation,oxidative stress,endoplasmic reticulum stress,and mitochondrial and synaptic dysfunction.Treatments targeting hypoxia may delay or mitigate the progression of AD.Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD.Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism,tau phosphorylation,neuroinflammation,neuronal apoptosis,oxidative stress,neurotrophic factors,mitochondrial function,cerebral blood volume,and protein synthesis.In this review,we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations.We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.展开更多
Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.How...Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.展开更多
Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation...Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.展开更多
Ligustrazine,an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort,has been clinically applied to treat the cerebrovascular diseases.Hyperhomocystcincmia(Hhcy)is an independent ...Ligustrazine,an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort,has been clinically applied to treat the cerebrovascular diseases.Hyperhomocystcincmia(Hhcy)is an independent risk factor for Alzheimer's disease(AD).Memory deficits can be caused by Hhcy via pathologies of Aβ-like tau and amyloid-β(Aβ)in the hippocampus.Here,we investigated whether homocysteine(Hey)can induce Aβ-like pathologies and the effects of ligustrazine on these pathologies.The Hey rat model was constructed by 14-day Hey injection via vena caudalis,and rats were treated with daily intragastric administration of ligustrazine at the same time.We found that the pathologies of tau and Aβ were induced by Hey in the hippocampus,while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine treatment.Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced Aβ-like pathologies.展开更多
Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mous...Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of mice.After the mice were sacrificed,the hippocampus was excised for further analysis.Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte.Western blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory cytokines.Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus.Absence of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD.However,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.展开更多
Progressive supranuclear palsy,corticobasal degeneration,multiple system atrophy and dementia with Lewy bodies are the most common causes of atypical Parkinsonism and enter the differential diagnosis of Parkinson'...Progressive supranuclear palsy,corticobasal degeneration,multiple system atrophy and dementia with Lewy bodies are the most common causes of atypical Parkinsonism and enter the differential diagnosis of Parkinson's disease.multiple system atrophy,dementia with Lewy bodies and Parkinson's disease are synucleinopathies,whereas progressive supranuclear palsy and corticobasal degeneration are tauopathies.Multiple cerebrospinal fluid markers have been applied on cohorts of patients with Parkinsonism,with the aim to develop biomarkers for these disorders.Total tau(τΤ),phosphorylated tau at threonine 181(τP-181)and amyloid-beta with 42 amino acids(Aβ42)are considered classical biomarkers for Alzheimer's disease.The aim of the present study is to review the literature regarding these classical cerebrospinal fluid biomarkers in cohorts with Parkinsonism,as well as present data on novel approaches regarding analysis of these proteins.展开更多
In light of the accelerated aging of the global population and the deterioration of the atmosphere pollution, we sought to clarify the potential mechanisms by which fine particulate matter(PM_(2.5)) can cause cognitiv...In light of the accelerated aging of the global population and the deterioration of the atmosphere pollution, we sought to clarify the potential mechanisms by which fine particulate matter(PM_(2.5)) can cause cognitive impairment and neurodegeneration through the alteration of mitochondrial structure and function. The results indicate that PM_(2.5) inhalation reduces ATP production by disrupting the aerobic tricarboxylic acid cycle and oxidative phosphorylation, thereby causing the hypophosphorylation of tau in the cortices of middle-aged mice. Furthermore, excessive reactive oxygen species generation was involved in the impairment. Interestingly, these alterations were partially reversed after exposure to PM_(2.5) ended. These findings clarify the mechanism involved in mitochondrial abnormality-related neuropathological dysfunction in response to atmospheric PM_(2.5) inhalation and provide an optimistic sight for alleviating the adverse health outcomes in polluted areas.展开更多
Objective:Alzheimer’s disease(AD)is along with cognitive decline due to amyloid-β(Aβ)plaques,tau hyperphospho rylation,and neuron loss.Shenqi Xingnao Granules(SQXN),a traditional Chinese medicine,significantly amel...Objective:Alzheimer’s disease(AD)is along with cognitive decline due to amyloid-β(Aβ)plaques,tau hyperphospho rylation,and neuron loss.Shenqi Xingnao Granules(SQXN),a traditional Chinese medicine,significantly ameliorated the cognitive function and daily living abilities of patients with AD.However,till date,no study has investigated the mechanism of action of SQXN on AD.The present study aimed to verify the effects of SQXN treatment on cognitive impairments and AD-like pathologies in APP/PS1 mice.Methods:Four-month-old APP/PS1 transgenic(Tg)mice were randomly divided into a model group and SQXN-treated(3.5,7,14 g/kg per day)groups.Learning-memory abilities were determined by Morris water maze and object recognition test.All mice were sacrificed and the brain samples were collected after 75 d.The soluble Aβcontents were detected by Elisa kit;The levels of expression of NeuN,APP,phosphorylated tau and related protein were measured by Western blotting;The inflammation factors were detected by the proinflammatory panel kit.Results:Four-month-old APP/PS1 mice were administered SQXN by oral gavage for 2.5 months.Using the Morris water maze tests and Novel object recognition,we found that SQXN restored behavioral deficits in the experimental group of Tg mice when compared with the controls.SQXN also inhibited neuronal loss(NeuN marker).SQXN treatment decreased soluble Aβ42 through inhibiting the expression of sAPPβand BACE-1 without regulating full-length amyloid precursor protein(FL APP).Insulin degrading enzyme(IDE),the Aβdegrading enzyme,were increased by SQXN.In addition,SQXN reduced hyperphosphorylated tau protein levels and prevented excessive activation of p-GSK-3βin the brain of APP/PS1 mice.Compared with APP/PS1 transgenic negative mice,IFN-γ,IL-1β,IL-2,IL-4,IL-5,IL-6,IL-12 p70,KC/GRO and TNF-αwere not obviously changed in the brain of 6.5-month-old APP/PS1 transgenic(Tg)mice.However,SQXN could inhibited the expression of IL-2.Conclusion:These results demonstrate that SQXN ameliorates the cognitive impairments in APP/PS1 mice.The possible mechanisms involve its inhibition of neuronal loss,soluble Aβdeposition,tau hyperphosphorylation and inflammation.展开更多
Background:Traumatic brain injury,one of the leading causes of death in adults under 40 years of age in the world,is frequently caused by mechanical shock,resulting in diffuse neuronal damage and long-term cognitive d...Background:Traumatic brain injury,one of the leading causes of death in adults under 40 years of age in the world,is frequently caused by mechanical shock,resulting in diffuse neuronal damage and long-term cognitive dysfunction.Many existing TBI animal models revival with expensive equipment or special room are needed or the processes of operations are complex and not easy to be widely used.Therefore,a simpler TBI model needs to be designed.Methods:Our TBI model is an innovation of the modeling method through air guns shutting rubber bullets.A core facet is the application of our designed rubber bullet impact device.It could focus the hitting power to the fixed site of the brain,thus triggering a mild closed head injury.Moreover,the degree of damage can be adjusted by the times of shots.Results:Our model induced blood-brain barrier leakage and diffused neuronal damage.Besides,it led to an increased level of Tau phosphorylation and resulted in cognitive dysfunction within several weeks post-injury.Conclusion:Our TBI model is not only simple and time-saving but also can simulate mild brain injuries in clinical.It is suitable for exploring pathobiological mechanisms as well as a screening of potential therapies for TBI.展开更多
基金supported by FONDECYT,No.11170546,CONICYT PAI,No.77170091(to CTR)FONDECYT,No.3210591(to CJ).
文摘During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Aging is one of the main risk factors for the development of neurodegenerative diseases,such as Alzheimer’s disease.One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates.The most studied brain aggregates are the senile plaques,formed by Aβpeptide;however,the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity.It is reported that neurons undergo severe mitochondrial dysfunction with age,with a decrease in adenosine 5′-triphosphate production,loss of the mitochondrial membrane potential,redox imbalance,impaired mitophagy,and loss of calcium buffer capacity.Interestingly,abnormal tau protein interacts with several mitochondrial proteins,suggesting that it could induce mitochondrial dysfunction.Nevertheless,whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown.A recent study of our laboratory shows that phosphorylated tau at Ser396/404(known as PHF-1),an epitope commonly related to pathology,accumulates inside mitochondria during normal aging.This accumulation occurs preferentially in synaptic mitochondria,which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals.Here,we review the main tau modifications promoting mitochondrial dysfunction,and the possible mechanism involved.Also,we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging.Finally,we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease,which could be considered as an early event in the neurodegenerative process.Thus,phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.
基金supported by the Ministry of Science and Technology of China(2018YFC1312300)the National Natural Science Foundation of China(81722016)。
文摘A lack of convenient and reliable biomarkers for diagnosis and prognosis is a common challenge for neurodegenerative diseases such as Alzheimer's disease(AD).Recent advancement in ultrasensitive protein assays has allowed the quantification of tau and phosphorylated tau proteins in peripheral plasma.Here we identified 66 eligible studies reporting quantification of plasma tau and phosphorylated tau 181(ptau181)using four ultrasensitive methods.Meta-analysis of these studies confirmed that the AD patients had significantly higher plasma tau and ptau181 levels compared with controls,and that the plasma tau and ptau181 could predict AD with high-accuracy area under curve of the Receiver Operating Characteristic Therefore,plasma tau and plasma ptau181 can be considered as biomarkers for AD diagnosis.
基金This work was supported by the Beijing Natural Science Foundation(7192016 and 7222064)the Scientific Research Common Program of Beijing Municipal Commission of Education(KM201910025029)the National Natural Science Foundation of China(82071539 and 31972911).
文摘Type 1 diabetes mellitus(T1DM)-induced cognitive dysfunction is common,but its underlying mechanisms are still poorly understood.In this study,we found that knockout of conventional protein kinase C(cPKC)γsignificantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles,but did not affect the activities of GSK-3βand PP2A in the hippocampal neurons of T1DM mice.cPKCγdeficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice.Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγdeficiency in T1DM mice.Moreover,cPKCγdeficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro.The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor.In conclusion,these results indicated that cPKCγpromotes autophagy through the AMPK/mTOR signaling pathway,thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.
基金This study was supported by a donation from the Erb family to the Beaumont Foundation,and by NIH grants R01AG17917,P30AG10161,and R01AG15819 to Dr.Bennett.
文摘Background:Tau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy,suggesting that therapies which increase anti-tau antibodies might slow the development and/or progression of Alzheimer’s disease(AD).The extent to which individuals with no cognitive impairment(NCI)possess serum anti-tau antibodies,and whether their concentrations of these antibodies differ from anti-tau antibody levels in persons with mild cognitive impairment(MCI)or AD,are unclear.Previous studies measuring these antibodies did not account for antibody polyvalent binding,which can be extensive,nor that antibody binding to phosphorylated tau peptides could be due to binding to non-phosphorylated epitopes on those peptides.Methods:An ELISA controlling for these factors was used to measure the specific binding of serum IgG and IgM to phosphorylated(“pTau;”phosphorylated at Serine-199 and Serine-202)and non-phosphorylated(“non-pTau”)tau 196-207 in subjects with NCI,MCI,or AD(n=10/group).Between-group differences in these antibody levels were evaluated for statistical significance,and correlations were examined in pooled data from all subjects between these antibody levels and subject age,global cognitive functioning,and NFT counts.Results:Specific IgG binding to pTau and non-pTau was detected in all subjects except for one NCI control.Specific IgM binding was detected to pTau in all subjects except for two AD patients,and to non-pTau in all subjects.Mean pTau IgG was increased in MCI subjects by 53% and 70% vs.AD and NCI subjects respectively(both p<0.05),while no significant differences were found between groups for non-pTau IgG(p=0.052),pTau IgM,or non-pTau IgM.Non-pTau IgG was negatively associated with global cognition(Spearman rho=−0.50).Conclusions:Specific binding of serum IgG and IgM to phosphorylated and non-phosphorylated tau may be present in older persons regardless of their cognitive status.Serum IgG to phosphorylated tau may be increased in individuals with MCI,but this unexpected finding requires confirmation.The approach used in this study to measure specific serum antibodies to phosphorylated tau should be useful for measuring antibodies to other post-translationally-modified proteins that are of relevance to neurodegenerative disorders.
基金supported by the National Natural Science Foundation of China (U2004134)Zhengzhou University (140/32310295) to NWH+2 种基金by Science Foundation Ireland(19/FFP/6437 and 14/IA/2571) to MJRa scholarship granted by the China Scholarship Council (CSC20200704504 7) to YY
文摘Cognitive decline in Alzheimer’s disease correlates with the extent of tau pathology,in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus.Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-βor long-term depression,a form of synaptic weakening involved in learning and memory,share similar mechanisms.Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging.Conversely,certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau,in particular,phosphorylation at residue Ser396.Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau(hyper)phosphorylation.We first summarize experimental evidence regarding tau-long-term depression interactions,followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer’s disease.Finally,we conclude with some thoughts and perspectives on future research about these interactions.
基金supported by the National Natural Science Foundation of China,No.81130080,31300942the National Key Basic Research Program of China(973 Program)+5 种基金No.2014CB542202the Natural Science Foundation of Jiangsu Province,China,No.BK20150409the Natural Science Foundation of Jiangsu Higher Education Institutions of China,No.15KJB180013the Scientific Research Foundation of Nantong University of China,No.14R29the Natural Science Foundation of Nantong City in China,No.MS12015043the Priority Academic Program Development of Jiangsu Higher Education Institutions of China
文摘Tau,a primary component of microtubule-associated protein,promotes microtubule assembly and/or disassembly and maintains the stability of the microtubule structure.Although the importance of tau in neurodegenerative diseases has been well demonstrated,whether tau is involved in peripheral nerve regeneration remains unknown.In the current study,we obtained sciatic nerve tissue from adult rats 0,1,4,7,and 14 days after sciatic nerve crush and examined tau m RNA and protein expression levels and the location of tau in the sciatic nerve following peripheral nerve injury.The results from our quantitative reverse transcription polymerase chain reaction analysis showed that compared with the uninjured control sciatic nerve,m RNA expression levels for both tau and tau tubulin kinase 1,a serine/threonine kinase that regulates tau phosphorylation,were decreased following peripheral nerve injury.Our western blot assay results suggested that the protein expression levels of tau and phosphorylated tau initially decreased 1 day post nerve injury but then gradually increased.The results of our immunohistochemical labeling showed that the location of tau protein was not altered by nerve injury.Thus,these results showed that the expression of tau was changed following sciatic nerve crush,suggesting that tau may be involved in peripheral nerve repair and regeneration.
基金Supported by National Natural Science Foundation of China(81673856,81573865)China Postdoctoral Science Foundation(2016M592319,2017T100542)+1 种基金Youth Project of Hubei University of Traditional Chinese Medicine(Zhong Yi Xiao Zi2015182)PhD Research Foundation of Hubei University of Traditional Chinese Medicine(Zhong Yi Dang Zi201425)
文摘[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was replicated by injection of Aβ_(25-35) in the left lateral ventricles of SD rats. The low dose( 25 mg/kg),middle dose( 50 mg/kg) and high dose( 100 mg/kg) notoginsenoside Rg1 was used for intragastric administration,respectively,two times every day. After 4 weeks,the Morris water maze test was done to detect the learning and memory capacity,and the immunoblotting,immunohistochemical methods were used to detect the changes in the phosphorylation level and distribution of tau protein in hippocampus of the rats. [Results] After the intracerebroventricular injection of Aβ_(25-35),the learning and memory capacity of the model rats was significantly lower than the learning and memory capacity of the normal control rats. The immunoblotting test results showed that the phosphorylation level of tau protein threonine 231 site( Thr231) in hippocampus was significantly increased,and the nonphosphorylation level was significantly decreased. The morphological testing results showed that the phosphorylation level of tau protein Thr231 of AD model rats was increased markedly in region of DG,CA1 and CA3 of the hippocampus. The intervention of the middle dose notoginsenoside Rg1 could significantly improve the learning and memory capacity of the model rats in Morris water maze. The notoginsenoside Rg1 in three different doses could all reduce the phosphorylation level of tau protein Thr231 in the hippocampal DG,CA1,CA3 regions,and there were no significant differences among the three doses. [Conclusions]The notoginsenoside Rg1 could improve Aβ_(25-35)-induced spatial learning and memory impairment of the AD model rats,and decreased the phosphorylation level of tau protein in hippocampus.
基金supported by the research foundation from Hubei Health and Family Planning Commission(No.WJ2015MB152)Natural Science Foundation of Hubei Province,China(No.2015CKC897 and No.2017CFA065)+1 种基金National Natural Science Foundation of China(No.81471304 and No.31771189)Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College,HUST
文摘Helicobacter pylori(H.pylori) infection is a recognized risk factor of dementia, while its role and mechanism in Alzheimer disease(AD) remained unclarified. Our previous study has identified that injection of soluble H.pylori filtrate could induce AD-like pathologic changes and cognitive impairment in SD rats. In the present study, we further explored the effect of long-term stomach colonization of H.pylori bacteria on the brains of SD rats. The results showed that H.pylori bacteria gavage induced an efficient colonization of H.pylori in the stomach after four weeks. However, there was no significant change of tau phosphorylation at Thr205(pT205), Thr231(pT231), Ser396(pS396) and Ser404(pS404) sites in the hippocampus and cerebral cortex. The H.pylori-infected rats also showed no cognitive impairment. These observations may result from inefficient release of bacterial pathogenic factors or the overall lack of host inflammatory responses. We conclude that SD rat with long-term H.pylori colonization in the stomach is not a suitable animal model for exploring the effects of H.pylori infection on brain function in human beings; administration of bacterial filtrates may better reveal the systemic pathologic changes induced by bacterial infection in animals which show a negative host response to bacterial colonization.
基金the Fundamental Research Funds for the Central Universities(No.lzujbky-2016-70)the Natural Science Foundation of Gansu Province(No.1506RJZA235).
文摘Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease(AD).However,there are currently no effective drugs that can target chronic stress to prevent AD.In this study,we explored the neuroprotective effect of hydroxysafflor yellow A(HSYA)against chronic mild stress(CMS)-induced memory impairments in mice and the underlying mechanism.The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice.HSYA increased the expression of brain-derived neurotrophic factor(BDNF)and activated downstream tropomyosin-related kinase B(TrkB)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling.HSYA decreased the expression of regulator of calcineurin 1-1L(RCAN1-1L)that could promote the activity of glycogen synthase kinase-3β(GSK-3β).HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3βand cyclin-dependent kinase-5(Cdk5).Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation,tau phosphorylation and memory impairments.HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.
基金This research was supported by National Natural Science Foundation of China(Nos.81473373,81874351,81673406)Capital Science and Technology Leading Talent Training Project(No.Z 191100006119017)+1 种基金Beijing Hospitals Authority Ascent Plan(No.DFL20190803)Cultivation Fund of Capital Medical University(No.PYZ19134).
文摘rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal hyperactivity behavior.Cornel iridoid glycoside(CIG)is an active ingredient extracted from Cornus officinalis,a traditional Chinese herb.The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity,and related mechanisms.The emotional hyperactivity was detected by locomotor activity test and Y maze test.Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau.Western blotting was used to detect the expression of related proteins.The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype,prevented neuronal loss,reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice.Meanwhile,CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors(NMDARs)subunits GluN1 and GluN2A andαamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunits GluA1 and GluA2,and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase IIα(p-CaMK IIα)in the brain of rTg4510 mice.In conclusion,CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.
基金supported by the Key Research and Development Support Project of Chengdu Science and Technology Bureau, No. 2019-YF05-00655-SN (to WDL)the Key Project of the Medical Science Department, University of Electronic Science and Technology of China, No. ZYGX2020ZB035 (to WDL)
文摘Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of side effects.Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD.Hypoxia is one of the important factors that contribute to the pathogenesis of AD.Multiple cellular processes synergistically promote hypoxia,including aging,hypertension,diabetes,hypoxia/obstructive sleep apnea,obesity,and traumatic brain injury.Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD,such as amyloid-beta metabolism,tau phosphorylation,autophagy,neuroinflammation,oxidative stress,endoplasmic reticulum stress,and mitochondrial and synaptic dysfunction.Treatments targeting hypoxia may delay or mitigate the progression of AD.Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD.Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism,tau phosphorylation,neuroinflammation,neuronal apoptosis,oxidative stress,neurotrophic factors,mitochondrial function,cerebral blood volume,and protein synthesis.In this review,we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations.We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.
基金financially supported by Shenzhen Sanming Project of Medicine and Health, No. SZSM201612049 (to KJC)the Shenzhen Municipal Basic Research Project for Discipline Layout of China, No. JCYJ20170413161352000 (to YHL)Guangdong Basic Research Project, No. 2020A1515011427 (to ZZW)
文摘Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.
基金supported by the Spanish Ministry of Industry and Competitiveness[Grant BFU2016-80006-P]The Andalusian Regional Government[Group BIO-216]the FEDER-Andalusian programme 2014-2020[1262530-R].
文摘Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.
基金grants from Changzhou Sci&Tech Program(No.CJ20190063,No.CJ20200090)Young Talent Development Plan of Changzhou Health Commission(No.CZQM2020078,and No.CZQM2020063)+3 种基金China Postdoctoral Science Foundation(No.2020M670012ZX)National Natural Science Foundation of China(No.81803498)Jiangsu Planned Projects for Postdoctoral Research Funds(No.2019K157)"Mass Entrepreneurship and Innovation Plan"of Jiangsu Province(No.QT201919).
文摘Ligustrazine,an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort,has been clinically applied to treat the cerebrovascular diseases.Hyperhomocystcincmia(Hhcy)is an independent risk factor for Alzheimer's disease(AD).Memory deficits can be caused by Hhcy via pathologies of Aβ-like tau and amyloid-β(Aβ)in the hippocampus.Here,we investigated whether homocysteine(Hey)can induce Aβ-like pathologies and the effects of ligustrazine on these pathologies.The Hey rat model was constructed by 14-day Hey injection via vena caudalis,and rats were treated with daily intragastric administration of ligustrazine at the same time.We found that the pathologies of tau and Aβ were induced by Hey in the hippocampus,while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine treatment.Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced Aβ-like pathologies.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)the Fundamental Research Funds for the Central Universities(YD9100002033)+1 种基金the Hefei Comprehensive National Science Center Hefei Brain Projectthe Natural Science Foundation of Anhui Province(2308085QH265)。
基金This study was partly supported by the National Natural Science Foundation of China(81771360).
文摘Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of mice.After the mice were sacrificed,the hippocampus was excised for further analysis.Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte.Western blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory cytokines.Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus.Absence of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD.However,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.
文摘Progressive supranuclear palsy,corticobasal degeneration,multiple system atrophy and dementia with Lewy bodies are the most common causes of atypical Parkinsonism and enter the differential diagnosis of Parkinson's disease.multiple system atrophy,dementia with Lewy bodies and Parkinson's disease are synucleinopathies,whereas progressive supranuclear palsy and corticobasal degeneration are tauopathies.Multiple cerebrospinal fluid markers have been applied on cohorts of patients with Parkinsonism,with the aim to develop biomarkers for these disorders.Total tau(τΤ),phosphorylated tau at threonine 181(τP-181)and amyloid-beta with 42 amino acids(Aβ42)are considered classical biomarkers for Alzheimer's disease.The aim of the present study is to review the literature regarding these classical cerebrospinal fluid biomarkers in cohorts with Parkinsonism,as well as present data on novel approaches regarding analysis of these proteins.
基金supported by the National Science Foundation of China(Nos.21377076,91543203,21477070,21222701)Specialized Research Fund for the Doctoral Program of Higher Education of China(Nos.20121401110003,20131401110005)+1 种基金Project Supported by Shanxi Young Sanjin Scholarship of China,Program for the Outstanding Innovative Teams of Higher Learning Institutions of ShanxiResearch Project Supported by Shanxi Scholarship Council of China(No.2015-006)
文摘In light of the accelerated aging of the global population and the deterioration of the atmosphere pollution, we sought to clarify the potential mechanisms by which fine particulate matter(PM_(2.5)) can cause cognitive impairment and neurodegeneration through the alteration of mitochondrial structure and function. The results indicate that PM_(2.5) inhalation reduces ATP production by disrupting the aerobic tricarboxylic acid cycle and oxidative phosphorylation, thereby causing the hypophosphorylation of tau in the cortices of middle-aged mice. Furthermore, excessive reactive oxygen species generation was involved in the impairment. Interestingly, these alterations were partially reversed after exposure to PM_(2.5) ended. These findings clarify the mechanism involved in mitochondrial abnormality-related neuropathological dysfunction in response to atmospheric PM_(2.5) inhalation and provide an optimistic sight for alleviating the adverse health outcomes in polluted areas.
基金supported by the State Key Program of National Natural Science of China(grant number 81430100)Beijing Hundred,Thousand and Ten Thousand Talent Project(grant number 2018A04)+1 种基金National Science Fund for Distinguished Young Scholars(grant number 81625025)Beijing Municipal Science&Technology Commission(grant number Z161100000216135)。
文摘Objective:Alzheimer’s disease(AD)is along with cognitive decline due to amyloid-β(Aβ)plaques,tau hyperphospho rylation,and neuron loss.Shenqi Xingnao Granules(SQXN),a traditional Chinese medicine,significantly ameliorated the cognitive function and daily living abilities of patients with AD.However,till date,no study has investigated the mechanism of action of SQXN on AD.The present study aimed to verify the effects of SQXN treatment on cognitive impairments and AD-like pathologies in APP/PS1 mice.Methods:Four-month-old APP/PS1 transgenic(Tg)mice were randomly divided into a model group and SQXN-treated(3.5,7,14 g/kg per day)groups.Learning-memory abilities were determined by Morris water maze and object recognition test.All mice were sacrificed and the brain samples were collected after 75 d.The soluble Aβcontents were detected by Elisa kit;The levels of expression of NeuN,APP,phosphorylated tau and related protein were measured by Western blotting;The inflammation factors were detected by the proinflammatory panel kit.Results:Four-month-old APP/PS1 mice were administered SQXN by oral gavage for 2.5 months.Using the Morris water maze tests and Novel object recognition,we found that SQXN restored behavioral deficits in the experimental group of Tg mice when compared with the controls.SQXN also inhibited neuronal loss(NeuN marker).SQXN treatment decreased soluble Aβ42 through inhibiting the expression of sAPPβand BACE-1 without regulating full-length amyloid precursor protein(FL APP).Insulin degrading enzyme(IDE),the Aβdegrading enzyme,were increased by SQXN.In addition,SQXN reduced hyperphosphorylated tau protein levels and prevented excessive activation of p-GSK-3βin the brain of APP/PS1 mice.Compared with APP/PS1 transgenic negative mice,IFN-γ,IL-1β,IL-2,IL-4,IL-5,IL-6,IL-12 p70,KC/GRO and TNF-αwere not obviously changed in the brain of 6.5-month-old APP/PS1 transgenic(Tg)mice.However,SQXN could inhibited the expression of IL-2.Conclusion:These results demonstrate that SQXN ameliorates the cognitive impairments in APP/PS1 mice.The possible mechanisms involve its inhibition of neuronal loss,soluble Aβdeposition,tau hyperphosphorylation and inflammation.
基金This work was supported by the National Natural Science Foundation of China(grant number 81671264)Guangzhou Scientific Foundation Committee(grant numbers 201704020222 and 201807010094)
文摘Background:Traumatic brain injury,one of the leading causes of death in adults under 40 years of age in the world,is frequently caused by mechanical shock,resulting in diffuse neuronal damage and long-term cognitive dysfunction.Many existing TBI animal models revival with expensive equipment or special room are needed or the processes of operations are complex and not easy to be widely used.Therefore,a simpler TBI model needs to be designed.Methods:Our TBI model is an innovation of the modeling method through air guns shutting rubber bullets.A core facet is the application of our designed rubber bullet impact device.It could focus the hitting power to the fixed site of the brain,thus triggering a mild closed head injury.Moreover,the degree of damage can be adjusted by the times of shots.Results:Our model induced blood-brain barrier leakage and diffused neuronal damage.Besides,it led to an increased level of Tau phosphorylation and resulted in cognitive dysfunction within several weeks post-injury.Conclusion:Our TBI model is not only simple and time-saving but also can simulate mild brain injuries in clinical.It is suitable for exploring pathobiological mechanisms as well as a screening of potential therapies for TBI.
