Objective To evaluate senile plaque formation and compare the sensitivity of three differentβ-amyloid(Aβ)labeling methods(antibody staining,Gallyas silver staining,and thioflavin-S staining)to detect Aβdeposition.M...Objective To evaluate senile plaque formation and compare the sensitivity of three differentβ-amyloid(Aβ)labeling methods(antibody staining,Gallyas silver staining,and thioflavin-S staining)to detect Aβdeposition.Methods APPswe/PSEN1dE9 transgenic mice(APP/PS1)of different ages were used to examine spatiotemporal changes in Aβplaque deposition.Antibody staining,Gallyas silver staining,and thioflavin-S staining were used to detect Aβplaque deposition in the same brain region of adjacent slices from model mice,and the results were compared.Results With aging,Aβplaques first appeared in the cortex and then the deposition increased throughout the whole brain.Significantly greater plaque deposition was detected by 6E10 antibody than that analyzed with Gallyas silver staining or thioflavin-S staining(P<0.05).Plaque deposition did not show significant difference between the APP/PS1 mice brains assayed with Gallyas silver staining and ones with thioflavin-S staining(P=0.0033).Conclusions The APP/PS1 mouse model of Alzheimer’s disease could mimick the progress of Aβplaques occurred in patients with Alzheimer’s disease.Antibody detection of Aβdeposition may be more sensitive than chemical staining methods.展开更多
Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hip...Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.展开更多
TMEM16F is involved in many physiological processes such as blood coagulation,cell membrane fusion and bone mineralization.Activation of TMEM16F has been studied in various central nervous system diseases.High TMEM16F...TMEM16F is involved in many physiological processes such as blood coagulation,cell membrane fusion and bone mineralization.Activation of TMEM16F has been studied in various central nervous system diseases.High TMEM16F level has been also found to participate in microglial phagocytosis and transformation.Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease.However,few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer’s disease.In this study,we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD.We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome.Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice.After TMEM16F knockdown in mice,spatial memory ability was improved,microglia polarization to the M2 phenotype was promoted,NLRP3 inflammasome activation was inhibited,cell apoptosis and Aβplaque deposition in brain tissue were reduced,and brain injury was alleviated.We used amyloid-beta(Aβ_(25-35))to stimulate human microglia to construct microglia models of Alzheimer’s disease.The levels of TMEM16F,inducible nitric oxide synthase(iNOS),proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ_(25-35) treated group compared with that in the control group.TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3,reduced the release of proinflammatory factors interleukin-1,interleukin-6 and tumor necrosis factor-α,and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1βand interleukin-18.This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin.Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer’s disease through participating in polarization of microglia and activation of the NLRP3 inflammasome.These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer’s disease treatment.展开更多
Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In...Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.展开更多
There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypoth...There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypothesis is one of the most widely accepted causes of AD.In this study,we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles(pSiNPs)as a therapeutic nano-platform to overcome AD.We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library.As a result of the in vitro assay of amyloid plaques and library screening,we confirmed that 6-amino-2-naphthalenesulfonic acid(ANA)showed the highest efficacy for plaque disaggregation as a hit compound.To confirm the targeted delivery of ANA to the AD brain,a nano-platform was created using porous silicon nanoparticles(pSiNPs)with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol(PEG)surface functionalization.The resulting nano-formulation,named Biotin-CaCl2-ANA-pSiNPs(BCAP),delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain.This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.展开更多
Peymnie＇s disease （PD） is most simply referred to as a fibrotic wound-healing disorder of the tunica albuginea. It is both a physically and psychologically devastating disorder that causes penile deformity, curvatu...Peymnie＇s disease （PD） is most simply referred to as a fibrotic wound-healing disorder of the tunica albuginea. It is both a physically and psychologically devastating disorder that causes penile deformity, curvature, hinging, narrowing and shortening, which may compromise sexual function. Although a variety of non-surgical treatments have been suggested, none to date offer a reliable and effective correction of the penile deformity. As a result, surgery remains the gold standard treatment option, offering the most rapid and reliable treatment which will be the focus of this article. We review the preoperative evaluation, surgical algorithm, graft materials and postoperative management of PD. Outcomes for tunical shortening, tunical lengthening and penile prosthesis placement for penile straightening are reviewed. Tunica albuginea plication is the preferred method of straightening for men with adequate rigidity and less severe disease defined as curvature less than 70° without narrowing/hinging. Men who have more severe, complex deformity, but maintain strong preoperative erectile function should be considered candidates for straightening with plaque incision or partial excision and grafting. Finally, for those men who have inadequate rigidity and PD, penile prosthesis placement with straightening is the best approach to address both problems.展开更多
Alzheimer＇s disease（AD）, a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42（Aβ42） plaques, which result in the onset of neurodegen...Alzheimer＇s disease（AD）, a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42（Aβ42） plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to（i） study etiology of disease,（ii） look for genetic modifiers, and（iii） identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer＇s disease.展开更多
基金Supported by the 2016 Major Collaborative Innovation Program of the Chinese Academy of Medical Sciences(2016-I2M-1004)
文摘Objective To evaluate senile plaque formation and compare the sensitivity of three differentβ-amyloid(Aβ)labeling methods(antibody staining,Gallyas silver staining,and thioflavin-S staining)to detect Aβdeposition.Methods APPswe/PSEN1dE9 transgenic mice(APP/PS1)of different ages were used to examine spatiotemporal changes in Aβplaque deposition.Antibody staining,Gallyas silver staining,and thioflavin-S staining were used to detect Aβplaque deposition in the same brain region of adjacent slices from model mice,and the results were compared.Results With aging,Aβplaques first appeared in the cortex and then the deposition increased throughout the whole brain.Significantly greater plaque deposition was detected by 6E10 antibody than that analyzed with Gallyas silver staining or thioflavin-S staining(P<0.05).Plaque deposition did not show significant difference between the APP/PS1 mice brains assayed with Gallyas silver staining and ones with thioflavin-S staining(P=0.0033).Conclusions The APP/PS1 mouse model of Alzheimer’s disease could mimick the progress of Aβplaques occurred in patients with Alzheimer’s disease.Antibody detection of Aβdeposition may be more sensitive than chemical staining methods.
基金supported by the National Natural Science Foundation of China,No.91849104(to YW)。
文摘Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.
基金supported by the National Natural Science Foundation of China,No.82072941(to QHX)Liaoning Province Key R&D Program Guidance Project,No.2020JH2/10300044Science and Technology Plan Project of Shenyang,No.20-205-4-050(both to XHS)。
文摘TMEM16F is involved in many physiological processes such as blood coagulation,cell membrane fusion and bone mineralization.Activation of TMEM16F has been studied in various central nervous system diseases.High TMEM16F level has been also found to participate in microglial phagocytosis and transformation.Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer’s disease.However,few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer’s disease.In this study,we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD.We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome.Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice.After TMEM16F knockdown in mice,spatial memory ability was improved,microglia polarization to the M2 phenotype was promoted,NLRP3 inflammasome activation was inhibited,cell apoptosis and Aβplaque deposition in brain tissue were reduced,and brain injury was alleviated.We used amyloid-beta(Aβ_(25-35))to stimulate human microglia to construct microglia models of Alzheimer’s disease.The levels of TMEM16F,inducible nitric oxide synthase(iNOS),proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ_(25-35) treated group compared with that in the control group.TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3,reduced the release of proinflammatory factors interleukin-1,interleukin-6 and tumor necrosis factor-α,and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1βand interleukin-18.This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin.Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer’s disease through participating in polarization of microglia and activation of the NLRP3 inflammasome.These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer’s disease treatment.
基金supported by the Notional Natural Science Foundation of China,Nos.81371213 and 8107098 7the Natural Science Foundation of Shanghai,No.21ZR1468400 (all to QLY)。
文摘Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.
基金supported by Basic Science Research Program through the National Research Foundation(NRF)of Korea funded by the Ministry of Education(2018-R1A6A1A03025124D.K.)+5 种基金supported by Bio&Medical Technology Development Program of the NRF of Korea funded by the Ministry of Science&ICT(2022-M3A9H1014157,2021-M3A9I5030523D.K.)a grant from Korea Health Technology R&D Project of the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(HI21C0239D.K.)supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(2022-R1F1A1069954D.K.).
文摘There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypothesis is one of the most widely accepted causes of AD.In this study,we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles(pSiNPs)as a therapeutic nano-platform to overcome AD.We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library.As a result of the in vitro assay of amyloid plaques and library screening,we confirmed that 6-amino-2-naphthalenesulfonic acid(ANA)showed the highest efficacy for plaque disaggregation as a hit compound.To confirm the targeted delivery of ANA to the AD brain,a nano-platform was created using porous silicon nanoparticles(pSiNPs)with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol(PEG)surface functionalization.The resulting nano-formulation,named Biotin-CaCl2-ANA-pSiNPs(BCAP),delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain.This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.
文摘Peymnie＇s disease （PD） is most simply referred to as a fibrotic wound-healing disorder of the tunica albuginea. It is both a physically and psychologically devastating disorder that causes penile deformity, curvature, hinging, narrowing and shortening, which may compromise sexual function. Although a variety of non-surgical treatments have been suggested, none to date offer a reliable and effective correction of the penile deformity. As a result, surgery remains the gold standard treatment option, offering the most rapid and reliable treatment which will be the focus of this article. We review the preoperative evaluation, surgical algorithm, graft materials and postoperative management of PD. Outcomes for tunical shortening, tunical lengthening and penile prosthesis placement for penile straightening are reviewed. Tunica albuginea plication is the preferred method of straightening for men with adequate rigidity and less severe disease defined as curvature less than 70° without narrowing/hinging. Men who have more severe, complex deformity, but maintain strong preoperative erectile function should be considered candidates for straightening with plaque incision or partial excision and grafting. Finally, for those men who have inadequate rigidity and PD, penile prosthesis placement with straightening is the best approach to address both problems.
文摘Alzheimer＇s disease（AD）, a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42（Aβ42） plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to（i） study etiology of disease,（ii） look for genetic modifiers, and（iii） identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer＇s disease.
