Amyloid beta-peptide 1-42(Aβ1-42)is one of the biomarkers of Alzheimer's disease,and its selective capture and quantitative detection are important for diagnosis and treatment of Alzheimer's disease.Herein,co...Amyloid beta-peptide 1-42(Aβ1-42)is one of the biomarkers of Alzheimer's disease,and its selective capture and quantitative detection are important for diagnosis and treatment of Alzheimer's disease.Herein,copper(Ⅱ)ions-immobilized virus-like hollow covalent organic frameworks(V-HCOFs@Cu^(2+))were synthesized by a facile approach.The as-prepared V-HCOFs@Cu^(2+)showed unique morphology,ultra-high specific surface(2552 m^(2)/g),uniform mesoporous structure(3.2 nm),superior chemical stability and abundant binding sites.Based on these excellent properties,the V-HCOFs@Cu^(2+)could be adopted as an ideal enrichment probe for highly efficient capture of Aβ1-42,exhibiting high adsorption capacity(320 mg/g),and fast adsorption equilibration time(3 min).In addition,an attractive approach of the V-HCOFs@Cu^(2+)-based matrix-assisted laser desorption/ionization mass spectrometry(MALDI-MS)was developed for the rapid screening and quantitative analysis of Aβ1-42 in human serum by using C-peptide as an internal standard,which exhibited low limit of detection(LOD,0.2 fmol/μL),and satisfactory recovery.This work provides an alternative solution for enrichment of biomarkers and also offers the potential applications of COFs in clinical analysis.展开更多
Amyloid 13-peptide, a major component of senile plaques in Alzheimer＇s disease, has been implicated in neuronal cell death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral isch...Amyloid 13-peptide, a major component of senile plaques in Alzheimer＇s disease, has been implicated in neuronal cell death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer＇s disease. In this study, a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries; meanwhile, fibrillar amyloid [3-peptide was injected into the rat lateral ventricle. The Morris water maze test and histological staining revealed that administration of amyloid 13-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury. Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 313 were significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid [3-peptide administration than those undergo- ing cerebral ischemia-repetfusion or amyloid 13-peptide administration alone. Conversely, the activ- ity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloid 13-peptide administration. These findings suggest that amyloid 13-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.展开更多
Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer＇s disease （AD）, which is pathologically characterized by the accumulation of senile plaques containing activated microg...Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer＇s disease （AD）, which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid β-peptides （Aβ）. In the present study, we examined the neuroprotective effects of hydrogen sulfide （H2S） on neuroinflammation in rats with Aβ1-40 hippocampal injection. We found that Aβ-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippocampal region compared with those in sham operated rats. NaHS （a donor of H2S, 5.6 mg/kg/d, i.p.） treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1β and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation pathway in the Aβ-induced rat model and has potential value for AD therapy.展开更多
Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensi...Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensis stem-leaf total flavonoid on amyloid beta-peptide-induced neuronal apoptosis and the expression of apoptosis-related proteins in the rat hippocampus. Male Wistar rats were given intragastric administration of Scutellaria baicalensis stem-leaf total flavonoid, 50 or 100 mg/kg, once per day. On day 8 after administration, 10 pg amyloid beta-peptide （25-35） was injected into the bilateral hippocampus of rats to induce neuronal apoptosis. On day 20, hippocampal tissue was harvested and probed with the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Scutellaria baicalensis stem-leaf total flavonoid at 50 and 100 mg/kg reduced neuronal apoptosis induced by amyloid beta-peptide （25-35） in the rat hippocampus. Immunohistochemistry and western blot assay revealed that expression of the pro-apoptotic protein Bax, cytochrome c and caspase-3 was significantly diminished by 50 and 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid, while expression of the anti-apoptotic protein Bcl-2 was increased. Moreover, 100 mg/kg Scutellana baicalensis stem-leaf total flavonoid had a more dramatic effect than the lower dosage. These experimental findings indicate that Scutellaria baicalensis stem-leaf total flavonoid dose-dependently attenuates neuronal apoptosis induced by amyloid beta-peptide in the hippocampus, and it might mediate this by regulating the expression of Bax, cytochrome c, caspase-3 and Bcl-2.展开更多
The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole n...The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H 13, acting as the anchoring site, and the backbone＇s deprotoned amide nitogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.展开更多
Amyloid-β 1-42(Aβ42)plays a pivotal role in Alzheimer disease(AD)pathogenesis. Peripheral clearance of Aβ42 largely affects its level in the brain and affects AD progression. Although nattokinase(NK)degrades Aβ40,...Amyloid-β 1-42(Aβ42)plays a pivotal role in Alzheimer disease(AD)pathogenesis. Peripheral clearance of Aβ42 largely affects its level in the brain and affects AD progression. Although nattokinase(NK)degrades Aβ40, the details of NK's capture of various Aβ species and reduction of plasma Aβ42/Aβ40 are uncharacterized. In this study, the Aβ42/Aβ40-degrading ability of NK was investigated using five Aβs and AD model mice. The C-terminal region of Aβ42/Aβ40(Gly29 to Val40)was primarily required for NK capture, and the integrated conformation in Aβ42/Aβ40 aggregates was a more efficient target for NK catalysis. Further, suspended Aβ42/Aβ40 oligomers were more easily captured by NK than suspended Aβ42/Aβ40 fibrils, while deposited Aβ42/Aβ40 fibrils recruited more NK than deposited Aβ42/Aβ40 oligomers. Although most NK was likely lost during NK uptake and/or entry into the blood, a small fraction of NK showed good plasma Aβ42/Aβ40-degrading efficacy after entering the blood due to NK's stability in the plasma of AD mice for at least 9 days. It was concluded that oral administration of NK is a feasible approach for peripheral Aβ42/Aβ40 clearance. This implies that NK might serve as an anti-Aβ42 agent for the treatment of Aβ42/Aβ40-related diseases such as AD.展开更多
Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, t...Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism（s） by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study,we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1-42. HN also attenuated Aβ1-42-induced tau hyperphosphorylation,apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A（PP2A）catalytic subunit and thereby activating PP2 A. HN also inhibited apoptosis and reduced the oxidativestress induced by Aβ1-42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1-42-induced AD-like pathological changes and memory deficits.展开更多
Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid ...Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid beta-peptide （25-35） （Aβ25-35）. In the present study, PC12 cells were cultured with different doses （0, 0.1, 1.0, 10 and 100 nmol/L） of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester, a Notch-1 signaling pathway inhibitor, for 30 minutes. Then cultured cells were induced with Aβ25-3s for 48 hours. Pretreatment of PC12 cells with high doses of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester （〉 10 nmol/L） prolonged the survival of PC12 cells after Aβ25-35 induction, decreased the expression of apoptosis-related proteins caspase-3, -8, -9, increased the activity of oxidative stress-related superoxide dismutase and catalase, inhibited the production of active oxygen, and reduced nuclear factor kappa B expression. This study indicates that the Notch-1 signaling pathway plays a pivotal role in Aβ25-35-induced PC12 apoptosis.展开更多
Amyloid-β(Aβ)and tau,the two hallmark proteins associated with Alzheimer’s disease(AD),exhibit distinct toxic effects but also interact synergistically within the disease pathology.The prevailing theory in AD patho...Amyloid-β(Aβ)and tau,the two hallmark proteins associated with Alzheimer’s disease(AD),exhibit distinct toxic effects but also interact synergistically within the disease pathology.The prevailing theory in AD pathology-the amyloid cascade hypothesis-highlights the pivotal role of increased processing of the amyloid precursor protein(APP).Initially cleaved by the majorβ-secretase(β-amyloid cleaving enzyme-1,BACE1)in the brain,then undergoes further cleavage by theγ-secretase complex,resulting in the production of Aβ_(40-42)and a set of intracellular C-terminal peptides known as Aβand APP intracellular domain(β-AICDs)and soluble amyloid precursor proteinβ(sAPPβ)(Orobets and Karamyshev,2023).展开更多
Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticula...Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tum...In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.展开更多
Collagenα3(IV)chains are one of the major constituent components of the basement membrane in the mammalian testis.Studies have shown that biologically active fragments,such as noncollagenase domain(NC1)-peptide,can b...Collagenα3(IV)chains are one of the major constituent components of the basement membrane in the mammalian testis.Studies have shown that biologically active fragments,such as noncollagenase domain(NC1)-peptide,can be released from the C-terminal region of collagenα3(IV)chains,possibly through the proteolytic action of metalloproteinase 9(MMP9).NC1-peptide was shown to promote blood-testis barrier(BTB)remodeling and fully developed spermatid(e.g.,sperm)release from the seminiferous epithelium because this bioactive peptide was capable of perturbing the organization of both actin-and microtubule(MT)-based cytoskeletons at the Sertoli cell-cell and also Sertoli-spermatid interface,the ultrastructure known as the basal ectoplasmic specialization(ES)and apical ES,respectively.More importantly,recent studies have shown that this NC1-peptide-induced effects on cytoskeletal organization in the testis are mediated through an activation of mammalian target of rapamycin complex 1/ribosomal protein S6/transforming retrovirus Akt1/2 protein(mTORC1/rpS6/Akt1/2)signaling cascade,involving an activation of cell division control protein 42 homolog(Cdc42)GTPase,but not Ras homolog family member A GTPase(RhoA),and the participation of end-binding protein 1(EB1),a microtubule plus(+)end tracking protein(+TIP),downstream.Herein,we critically evaluate these findings,providing a critical discussion by which the basement membrane modulates spermatogenesis through one of its locally generated regulatory peptides in the testis.展开更多
Cariogenic Streptococcus mutans(S.mutans)is a leading cause of bacterial-induced oral diseases.Current strategies to kill bacteria based on Host defense peptide(HDP)mimicking polymers hold promise to treat oral bacter...Cariogenic Streptococcus mutans(S.mutans)is a leading cause of bacterial-induced oral diseases.Current strategies to kill bacteria based on Host defense peptide(HDP)mimicking polymers hold promise to treat oral bacterial infection.Here,we explore the impact of hydrophobic subunit and chain length variation on the antibacterial and antibiofilm activity ofβ-peptide polymers.The physicochemical and biological prop-erties,such as the toxicity,the antibacterial activity,and the effect on bacterial transcription ofβ-peptide polymers,were systematically investigated with numerous techniques.The results exhibited that the op-timalβ-peptide polymer has low toxicity towards human periodontal ligament fibroblasts,andβ-peptide polymers(especially P3)have more excellent antibacterial activity against S.mutans than metronidazole.In addition,β-peptide polymers inhibited the reversible and irreversible bacterial adhesion during the formation of biofilms.The polymer can promote biofilm dispersion by decreasing the hydrophobicity of bacterial cells after adhering to cell surfaces.Analysis of the transcriptome for S.mutans treated withβ-peptide polymers demonstrated thatβ-peptide polymers could reduce the cariogenicity of S.mutans by impacting the transcription of the energy and acid metabolism-related genes.β-peptide polymers are promising antimicrobial agents in clinical dentistry due to their high antibacterial efficiency and low tox-icity.展开更多
Objective： To improve DC-based tumor vaccination, we studied whether dendritic ceils （DCs） which cocultured with H22 liver cancer cells-derived heat shock protein （HSP） glycoprotein 96 （gp96） affect the T cell-...Objective： To improve DC-based tumor vaccination, we studied whether dendritic ceils （DCs） which cocultured with H22 liver cancer cells-derived heat shock protein （HSP） glycoprotein 96 （gp96） affect the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Methods： Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4, which mimiced the immunostimulatory effect of DC. Cocultured DC and gp96-peptide complexes were used to vaccine H22 liver cancer cells of mice. Using murine models we compared the immunogenecity of DC modified by gp96-peptides complexes derived from murine liver cancer cells alone or inactive tumor cells. To verify the specificity of the vaccine, in vitro assays were executed. Serum cytokine levels were quantified to explore the supposed pathway of DC modified by gp96 peptide complexes and its effect on antitumor immune response. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can induce potent tumor-antigenspecific immune response, augment the proliferation of Thl cells, and inhibit tumor growth. Conclusion： In this study, we have developed a novel DC-mediated tumor vaccine by combing the gp96 antigenic peptides complexes and inducing immune response against specific tumor cells, gp96 can be identified as a potent DC activator.展开更多
Objective： To investigate the antitumor effect of dendritic cell （DC） modified by gp96-peptide complexes both in vitro and in vivo. Methods：Gp96-peptide complexes were acquired from H22 liver cancer cells in mice....Objective： To investigate the antitumor effect of dendritic cell （DC） modified by gp96-peptide complexes both in vitro and in vivo. Methods：Gp96-peptide complexes were acquired from H22 liver cancer cells in mice. DC were cultured from bone marrow cells and modified by gp96-peptide complexes. Spleen lymphocytes of mice were activated by modified DC and the cytotoxicity were detected by ^51Cr release method. Modified DC, gp96-peptide complexes and inactivated H22 cells were injected into mice bearing H22 liver cancer cells to observe the levels of IL-10, IFN-y in serum and the alteration of proportions of CD8^＋-IFNy^＋ and CD8^＋-IL-10^＋ cells, CD4^＋-IFNy^＋ and CD4^＋-IL-10^＋ cells. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can improve the host＇s antitumor immune response and the proportions of Thl cells, inhibiting tumor growth. Conclusion： Gp96-peptide complexes can activate DC effectively, making DC a good vaccine.展开更多
Autophagy directly regulates the amyloid beta-peptide(Aβ)clearance,and its dysfunction occurs in the early pathogenesis of Alzheimer's disease(AD).We previously reported that docosahexaenoic acid-acylated astaxan...Autophagy directly regulates the amyloid beta-peptide(Aβ)clearance,and its dysfunction occurs in the early pathogenesis of Alzheimer's disease(AD).We previously reported that docosahexaenoic acid-acylated astaxanthin monoester(AST-DHA)showed neuroprotection against AD pathology.However,its in-depth mechanism and autophagic responses in AD brains are poorly understood.Herein,SH-SY5Y cells overexpressing the Swedish mutation(K595N/M596L)of APP gene were established to preliminarily evaluate the actions of AST-DHA on reducing Aβ_(1-42)levels and regulating autophagy.In microglial BV2 cells,AST-DHA and free astaxanthin(F-AST)recovered p62 and LC3Ⅱ/Ⅰlevels,and restored autophagy flux by rescuing the late phase of microglial autophagy.Notably,autophagic inhibitor bafilomycin A1 blunted the abilities of AST-DHA to reduce Aβ_(1-42)and fibral Aβ,suggesting that AST-DHA probably promoted Aβclearance in a microglial autophagy-dependent manner.Further studies in APP/PS1 mice verified that dietary AST-DHA and F-AST promoted Aβphagocytosis via microglial autophagy.Significant decreases of Iba1 and p62 were observed around Aβplaque in the hippocampus and cortex using triple fluorescence staining.Furthermore,AST-DHA exhibited superior performance over F-AST in restoring autophagic dysfunction,ameliorating Aβburden and cognitive deficit.Our findings suggest a possible mechanism of AST-DHA in improving AD by which it restores microglial autophagy to facilitate cerebral Aβclearance.It supports the future application of AST-DHA as an autophagic regulator in maintaining brain function.展开更多
Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peri...Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.展开更多
Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are th...Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are the deposition of amyloid plaques(composed of amyloid-beta,Aβ)and neurofibrillary tangles containing hyperphosphorylated Tau in the brain,accompanied by neu ronal and synaptic loss,neuroinflammation and brain atrophy(Jellinger,2022).Regardless of these common traits,growing evidence shows increased heterogen eity in the brain of AD patients considering both clinical manifestations and pathological features.展开更多
The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic prote...The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).展开更多
基金supported by a grant from the National Natural Science Foundation of China(Nos.21974021,22036001,and 91843301).
文摘Amyloid beta-peptide 1-42(Aβ1-42)is one of the biomarkers of Alzheimer's disease,and its selective capture and quantitative detection are important for diagnosis and treatment of Alzheimer's disease.Herein,copper(Ⅱ)ions-immobilized virus-like hollow covalent organic frameworks(V-HCOFs@Cu^(2+))were synthesized by a facile approach.The as-prepared V-HCOFs@Cu^(2+)showed unique morphology,ultra-high specific surface(2552 m^(2)/g),uniform mesoporous structure(3.2 nm),superior chemical stability and abundant binding sites.Based on these excellent properties,the V-HCOFs@Cu^(2+)could be adopted as an ideal enrichment probe for highly efficient capture of Aβ1-42,exhibiting high adsorption capacity(320 mg/g),and fast adsorption equilibration time(3 min).In addition,an attractive approach of the V-HCOFs@Cu^(2+)-based matrix-assisted laser desorption/ionization mass spectrometry(MALDI-MS)was developed for the rapid screening and quantitative analysis of Aβ1-42 in human serum by using C-peptide as an internal standard,which exhibited low limit of detection(LOD,0.2 fmol/μL),and satisfactory recovery.This work provides an alternative solution for enrichment of biomarkers and also offers the potential applications of COFs in clinical analysis.
基金supported by the National High Technology Research and Development Program of China("863"Program),No.2012AA020905the National Natural Science Foundation of China,No.81171143 and30971011+1 种基金National Natural Science Foundation of China(NSFC)/Research Grants Council(RGC) Joint Research Scheme,No.81161160570TsinghuaYue-Yuen Medical Sciences Fund
文摘Amyloid 13-peptide, a major component of senile plaques in Alzheimer＇s disease, has been implicated in neuronal cell death and cognitive impairment. Recently, studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer＇s disease. In this study, a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries; meanwhile, fibrillar amyloid [3-peptide was injected into the rat lateral ventricle. The Morris water maze test and histological staining revealed that administration of amyloid 13-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury. Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 313 were significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid [3-peptide administration than those undergo- ing cerebral ischemia-repetfusion or amyloid 13-peptide administration alone. Conversely, the activ- ity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloid 13-peptide administration. These findings suggest that amyloid 13-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions(No.Jx10131801095 to HongZhou)
文摘Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer＇s disease （AD）, which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid β-peptides （Aβ）. In the present study, we examined the neuroprotective effects of hydrogen sulfide （H2S） on neuroinflammation in rats with Aβ1-40 hippocampal injection. We found that Aβ-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippocampal region compared with those in sham operated rats. NaHS （a donor of H2S, 5.6 mg/kg/d, i.p.） treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1β and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation pathway in the Aβ-induced rat model and has potential value for AD therapy.
基金supported by grants from Hebei Provincial Science and Technology Bureau,No.08276101D-21
文摘Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensis stem-leaf total flavonoid on amyloid beta-peptide-induced neuronal apoptosis and the expression of apoptosis-related proteins in the rat hippocampus. Male Wistar rats were given intragastric administration of Scutellaria baicalensis stem-leaf total flavonoid, 50 or 100 mg/kg, once per day. On day 8 after administration, 10 pg amyloid beta-peptide （25-35） was injected into the bilateral hippocampus of rats to induce neuronal apoptosis. On day 20, hippocampal tissue was harvested and probed with the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Scutellaria baicalensis stem-leaf total flavonoid at 50 and 100 mg/kg reduced neuronal apoptosis induced by amyloid beta-peptide （25-35） in the rat hippocampus. Immunohistochemistry and western blot assay revealed that expression of the pro-apoptotic protein Bax, cytochrome c and caspase-3 was significantly diminished by 50 and 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid, while expression of the anti-apoptotic protein Bcl-2 was increased. Moreover, 100 mg/kg Scutellana baicalensis stem-leaf total flavonoid had a more dramatic effect than the lower dosage. These experimental findings indicate that Scutellaria baicalensis stem-leaf total flavonoid dose-dependently attenuates neuronal apoptosis induced by amyloid beta-peptide in the hippocampus, and it might mediate this by regulating the expression of Bax, cytochrome c, caspase-3 and Bcl-2.
基金This work was supported by the National Natural Science Foundation of China(Nos.30470408 and 20637010).
文摘The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H 13, acting as the anchoring site, and the backbone＇s deprotoned amide nitogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.
基金supported by the National Natural Science Foundation of China Program (No. 31970883)。
文摘Amyloid-β 1-42(Aβ42)plays a pivotal role in Alzheimer disease(AD)pathogenesis. Peripheral clearance of Aβ42 largely affects its level in the brain and affects AD progression. Although nattokinase(NK)degrades Aβ40, the details of NK's capture of various Aβ species and reduction of plasma Aβ42/Aβ40 are uncharacterized. In this study, the Aβ42/Aβ40-degrading ability of NK was investigated using five Aβs and AD model mice. The C-terminal region of Aβ42/Aβ40(Gly29 to Val40)was primarily required for NK capture, and the integrated conformation in Aβ42/Aβ40 aggregates was a more efficient target for NK catalysis. Further, suspended Aβ42/Aβ40 oligomers were more easily captured by NK than suspended Aβ42/Aβ40 fibrils, while deposited Aβ42/Aβ40 fibrils recruited more NK than deposited Aβ42/Aβ40 oligomers. Although most NK was likely lost during NK uptake and/or entry into the blood, a small fraction of NK showed good plasma Aβ42/Aβ40-degrading efficacy after entering the blood due to NK's stability in the plasma of AD mice for at least 9 days. It was concluded that oral administration of NK is a feasible approach for peripheral Aβ42/Aβ40 clearance. This implies that NK might serve as an anti-Aβ42 agent for the treatment of Aβ42/Aβ40-related diseases such as AD.
基金supported by the National Natural Science Foundation of China (81271402,31171028)Fundamental Research Funds for the Central Universities,China (2012QN130)
文摘Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism（s） by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study,we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1-42. HN also attenuated Aβ1-42-induced tau hyperphosphorylation,apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A（PP2A）catalytic subunit and thereby activating PP2 A. HN also inhibited apoptosis and reduced the oxidativestress induced by Aβ1-42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1-42-induced AD-like pathological changes and memory deficits.
文摘Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid beta-peptide （25-35） （Aβ25-35）. In the present study, PC12 cells were cultured with different doses （0, 0.1, 1.0, 10 and 100 nmol/L） of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester, a Notch-1 signaling pathway inhibitor, for 30 minutes. Then cultured cells were induced with Aβ25-3s for 48 hours. Pretreatment of PC12 cells with high doses of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester （〉 10 nmol/L） prolonged the survival of PC12 cells after Aβ25-35 induction, decreased the expression of apoptosis-related proteins caspase-3, -8, -9, increased the activity of oxidative stress-related superoxide dismutase and catalase, inhibited the production of active oxygen, and reduced nuclear factor kappa B expression. This study indicates that the Notch-1 signaling pathway plays a pivotal role in Aβ25-35-induced PC12 apoptosis.
文摘Amyloid-β(Aβ)and tau,the two hallmark proteins associated with Alzheimer’s disease(AD),exhibit distinct toxic effects but also interact synergistically within the disease pathology.The prevailing theory in AD pathology-the amyloid cascade hypothesis-highlights the pivotal role of increased processing of the amyloid precursor protein(APP).Initially cleaved by the majorβ-secretase(β-amyloid cleaving enzyme-1,BACE1)in the brain,then undergoes further cleavage by theγ-secretase complex,resulting in the production of Aβ_(40-42)and a set of intracellular C-terminal peptides known as Aβand APP intracellular domain(β-AICDs)and soluble amyloid precursor proteinβ(sAPPβ)(Orobets and Karamyshev,2023).
基金funded by the Russian Science Foundation(grant No.23-74-10092)(to AIS)。
文摘Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
文摘In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.
基金This work was supported in part by grants from the National Institutes of Health(NICHD,R01 HD056034 to CYC)the National Natural Science Foundation of China(NSFCNo.81730042 to RSG).
文摘Collagenα3(IV)chains are one of the major constituent components of the basement membrane in the mammalian testis.Studies have shown that biologically active fragments,such as noncollagenase domain(NC1)-peptide,can be released from the C-terminal region of collagenα3(IV)chains,possibly through the proteolytic action of metalloproteinase 9(MMP9).NC1-peptide was shown to promote blood-testis barrier(BTB)remodeling and fully developed spermatid(e.g.,sperm)release from the seminiferous epithelium because this bioactive peptide was capable of perturbing the organization of both actin-and microtubule(MT)-based cytoskeletons at the Sertoli cell-cell and also Sertoli-spermatid interface,the ultrastructure known as the basal ectoplasmic specialization(ES)and apical ES,respectively.More importantly,recent studies have shown that this NC1-peptide-induced effects on cytoskeletal organization in the testis are mediated through an activation of mammalian target of rapamycin complex 1/ribosomal protein S6/transforming retrovirus Akt1/2 protein(mTORC1/rpS6/Akt1/2)signaling cascade,involving an activation of cell division control protein 42 homolog(Cdc42)GTPase,but not Ras homolog family member A GTPase(RhoA),and the participation of end-binding protein 1(EB1),a microtubule plus(+)end tracking protein(+TIP),downstream.Herein,we critically evaluate these findings,providing a critical discussion by which the basement membrane modulates spermatogenesis through one of its locally generated regulatory peptides in the testis.
基金supported by the National Natural Science Foundation of China(No.51871050)the National Natural Science Foundation of China(No.U2106206)+3 种基金the Natural Science Foundation of Liaoning Province(No.20180510041)the Liaon-ing Revitalization Talents Program(No.XLYC1907158)the Gen-eral Project of Natural Science Foundation of Science and Tech-nology Department of Liaoning Province(No.2021-MS-308)the Fundamental Research Funds for the Central Universities(No.N2120007).
文摘Cariogenic Streptococcus mutans(S.mutans)is a leading cause of bacterial-induced oral diseases.Current strategies to kill bacteria based on Host defense peptide(HDP)mimicking polymers hold promise to treat oral bacterial infection.Here,we explore the impact of hydrophobic subunit and chain length variation on the antibacterial and antibiofilm activity ofβ-peptide polymers.The physicochemical and biological prop-erties,such as the toxicity,the antibacterial activity,and the effect on bacterial transcription ofβ-peptide polymers,were systematically investigated with numerous techniques.The results exhibited that the op-timalβ-peptide polymer has low toxicity towards human periodontal ligament fibroblasts,andβ-peptide polymers(especially P3)have more excellent antibacterial activity against S.mutans than metronidazole.In addition,β-peptide polymers inhibited the reversible and irreversible bacterial adhesion during the formation of biofilms.The polymer can promote biofilm dispersion by decreasing the hydrophobicity of bacterial cells after adhering to cell surfaces.Analysis of the transcriptome for S.mutans treated withβ-peptide polymers demonstrated thatβ-peptide polymers could reduce the cariogenicity of S.mutans by impacting the transcription of the energy and acid metabolism-related genes.β-peptide polymers are promising antimicrobial agents in clinical dentistry due to their high antibacterial efficiency and low tox-icity.
基金Supported by the National Natural Science Foundation of China (No. 30200369)
文摘Objective： To improve DC-based tumor vaccination, we studied whether dendritic ceils （DCs） which cocultured with H22 liver cancer cells-derived heat shock protein （HSP） glycoprotein 96 （gp96） affect the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Methods： Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4, which mimiced the immunostimulatory effect of DC. Cocultured DC and gp96-peptide complexes were used to vaccine H22 liver cancer cells of mice. Using murine models we compared the immunogenecity of DC modified by gp96-peptides complexes derived from murine liver cancer cells alone or inactive tumor cells. To verify the specificity of the vaccine, in vitro assays were executed. Serum cytokine levels were quantified to explore the supposed pathway of DC modified by gp96 peptide complexes and its effect on antitumor immune response. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can induce potent tumor-antigenspecific immune response, augment the proliferation of Thl cells, and inhibit tumor growth. Conclusion： In this study, we have developed a novel DC-mediated tumor vaccine by combing the gp96 antigenic peptides complexes and inducing immune response against specific tumor cells, gp96 can be identified as a potent DC activator.
基金Supported by National Natural Science Foundation of Chi-na (NO.30200369)
文摘Objective： To investigate the antitumor effect of dendritic cell （DC） modified by gp96-peptide complexes both in vitro and in vivo. Methods：Gp96-peptide complexes were acquired from H22 liver cancer cells in mice. DC were cultured from bone marrow cells and modified by gp96-peptide complexes. Spleen lymphocytes of mice were activated by modified DC and the cytotoxicity were detected by ^51Cr release method. Modified DC, gp96-peptide complexes and inactivated H22 cells were injected into mice bearing H22 liver cancer cells to observe the levels of IL-10, IFN-y in serum and the alteration of proportions of CD8^＋-IFNy^＋ and CD8^＋-IL-10^＋ cells, CD4^＋-IFNy^＋ and CD4^＋-IL-10^＋ cells. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can improve the host＇s antitumor immune response and the proportions of Thl cells, inhibiting tumor growth. Conclusion： Gp96-peptide complexes can activate DC effectively, making DC a good vaccine.
基金supported by the National Natural Science Foundation of China(32302063)Shandong Provincial Natural Science Foundation(ZR2023QC130)。
文摘Autophagy directly regulates the amyloid beta-peptide(Aβ)clearance,and its dysfunction occurs in the early pathogenesis of Alzheimer's disease(AD).We previously reported that docosahexaenoic acid-acylated astaxanthin monoester(AST-DHA)showed neuroprotection against AD pathology.However,its in-depth mechanism and autophagic responses in AD brains are poorly understood.Herein,SH-SY5Y cells overexpressing the Swedish mutation(K595N/M596L)of APP gene were established to preliminarily evaluate the actions of AST-DHA on reducing Aβ_(1-42)levels and regulating autophagy.In microglial BV2 cells,AST-DHA and free astaxanthin(F-AST)recovered p62 and LC3Ⅱ/Ⅰlevels,and restored autophagy flux by rescuing the late phase of microglial autophagy.Notably,autophagic inhibitor bafilomycin A1 blunted the abilities of AST-DHA to reduce Aβ_(1-42)and fibral Aβ,suggesting that AST-DHA probably promoted Aβclearance in a microglial autophagy-dependent manner.Further studies in APP/PS1 mice verified that dietary AST-DHA and F-AST promoted Aβphagocytosis via microglial autophagy.Significant decreases of Iba1 and p62 were observed around Aβplaque in the hippocampus and cortex using triple fluorescence staining.Furthermore,AST-DHA exhibited superior performance over F-AST in restoring autophagic dysfunction,ameliorating Aβburden and cognitive deficit.Our findings suggest a possible mechanism of AST-DHA in improving AD by which it restores microglial autophagy to facilitate cerebral Aβclearance.It supports the future application of AST-DHA as an autophagic regulator in maintaining brain function.
基金supported by grants from NIH(RF1AG072491 and R01AI132695)to RM.
文摘Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are the deposition of amyloid plaques(composed of amyloid-beta,Aβ)and neurofibrillary tangles containing hyperphosphorylated Tau in the brain,accompanied by neu ronal and synaptic loss,neuroinflammation and brain atrophy(Jellinger,2022).Regardless of these common traits,growing evidence shows increased heterogen eity in the brain of AD patients considering both clinical manifestations and pathological features.
基金funded by the Spanish Ministry of Science and Innovation(PDC2021-120914-I00)the Universitat Autònoma de Barcelona(PROOF OF CONCEPT 2020)ICREA,ICREA-Academia 2015 and 2020(to SV).
文摘The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).
