Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly con...Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.展开更多
Okadaic acid： Okadaic acid （OKA）, a polyether （C38 fatty acid） toxin, is a potent and selective inhibitor of protein phosphatase, PP1 and protein phosphatase 2A （PP2A）. It is mainly extracted from a black spong...Okadaic acid： Okadaic acid （OKA）, a polyether （C38 fatty acid） toxin, is a potent and selective inhibitor of protein phosphatase, PP1 and protein phosphatase 2A （PP2A）. It is mainly extracted from a black sponge Hallichondria okadaii and has been suggested to play a potent probe for studying the various molecular, cellular, biochemical and mechanism of neurotoxicity. It is known as a selective and potent in- hibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. It has been reported that Alzheimer＇s disease （AD） is a complex multi- factorial neurodegenerative disorder and hyperphosphor- ylated tau protein is a major pathological hallmark of AD. The reduced activity of phosphatases like, PP2A has been implicated in the brain of AD patients. OKA also induced inhibition of protein phosphatases cause neurofibrillary tangles （NFTs） like pathological changes and tau hyperphos- phorylation seen in AD pathology. Our and others reports inferred that OKA induces neurodegeneration along with tau hyperphosphorylation, GSK3β activation, oxidative stress, neuroinflammation and neurotoxicity which are char- acteristic of AD pathology （Figure 1）.展开更多
Alzheimer＇s disease（AD）is a fatal progressive neurodegenerative disorder characterized by loss in memory,cognition,and executive function and activities of daily living.AD pathogenesis has been shown to involve los...Alzheimer＇s disease（AD）is a fatal progressive neurodegenerative disorder characterized by loss in memory,cognition,and executive function and activities of daily living.AD pathogenesis has been shown to involve loss of neurons and synapses,cholinergic deficits,amyloid-beta protein（Aβ）deposition,tau protein hyperphosphorylation, and neuroinflammation.展开更多
Objective To explore the therapeutic effect and mechanism of Bushen Tiansui Decoction(补肾填髓方,BSTSD)and its active component icariin on Alzheimer’s disease(AD).Methods(i)Animal experiments.This study conducted exp...Objective To explore the therapeutic effect and mechanism of Bushen Tiansui Decoction(补肾填髓方,BSTSD)and its active component icariin on Alzheimer’s disease(AD).Methods(i)Animal experiments.This study conducted experiments using specific pathogen-free(SPF)grade male C57BL/6J wild-type(WT)mice and APP/PS1 double transgenic mice.The animals were divided into three groups:WT group(WT mice,n=5,receiving distilled wa-ter daily),APP/PS1 group(APP/PS1 double transgenic mice,n=5,receiving distilled water daily),and BSTSD group[APP/PS1 double transgenic mice,n=5,treated with BSTSD suspen-sion at a dosage of 27 g/(kg·d)for 90 d].Cognitive function was assessed using the Morris wa-ter maze(MWM).Post-experiment,hippocampal tissues were collected for analysis of pyra-midal cell and synaptic morphology through hematoxylin-eosin(HE)staining and transmis-sion electron microscopy(TEM).(ii)Cell experiments.The HT-22 cells were divided into con-trol group(untreated),Aβ_(25-35) group(treated with 20μmol/L Aβ_(25-35) for 24 h),icariin group(pre-treated with 20μmol/L icariin for 60 min,followed by 20μmol/L Aβ_(25-35) for an additional 24 h),and icariin+LY294002 group[treated with 20μmol/L icariin and 20μmol/L LY294002(an inhibitor of the phosphoinostitide 3-kinases(PI3K)signaling pathway)for 60 min,then exposed to 20μmol/L Aβ_(25-35) for 24 h],and cell viability was measured.Western blot was used to detect the expression levels of synapse-associated proteins[synaptophysin(SYP)and post-synaptic density-95(PSD-95)]and PI3K signaling pathway associated proteins[phosphorylat-ed(p)-PI3K/PI3K,p-protein kinase B(Akt)/Akt,and p-mechanistic target of rapamycin(mTOR)/mTOR].Results(i)Animal experiments.Compared with APP/PS1 group,BSTSD group showed that escape latency was significantly shortened(P<0.01)and the frequency of crossing the origi-nal platform was significantly increased(P<0.01).Morphological observation showed that pyramidal cells in the hippocampal CA1 region were arranged more regularly,nuclear stain-ing was uniform,and vacuole-like changes were reduced after BSTSD treatment.TEM showed that the length of synaptic active zone in BSTSD treatment group was increased com-pared with APP/PS1 group(P<0.01),and the width of synaptic gap was decreased(P<0.01).(ii)Cell experiments.Icariin had no obvious toxicity to HT-22 cells when the concentration was not more than 20μmol/L(P>0.05),and alleviated the cell viability decline induced by Aβ_(25-35)(P<0.01).Western blot results showed that compared with Aβ_(25-35) group,the ratios of p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR in icariin group were significantly increased(P<0.01),while the protein expression levels of SYP and PSD-95 were increased(P<0.01).These effects were blocked by LY294002(P<0.01).Conclusion BSTSD and icariin enhance cognitive function and synaptic integrity in AD mod-els and provide potential therapeutic strategies through activation of the PI3K/Akt/mTOR pathway.展开更多
Our purpose in this study was to develop an automated method for measuring three-dimensional (3D) cerebral cortical thicknesses in patients with Alzheimer’s disease (AD) using magnetic resonance (MR) images. Our prop...Our purpose in this study was to develop an automated method for measuring three-dimensional (3D) cerebral cortical thicknesses in patients with Alzheimer’s disease (AD) using magnetic resonance (MR) images. Our proposed method consists of mainly three steps. First, a brain parenchymal region was segmented based on brain model matching. Second, a 3D fuzzy membership map for a cerebral cortical region was created by applying a fuzzy c-means (FCM) clustering algorithm to T1-weighted MR images. Third, cerebral cortical thickness was three- dimensionally measured on each cortical surface voxel by using a localized gradient vector trajectory in a fuzzy membership map. Spherical models with 3 mm artificial cortical regions, which were produced using three noise levels of 2%, 5%, and 10%, were employed to evaluate the proposed method. We also applied the proposed method to T1-weighted images obtained from 20 cases, i.e., 10 clinically diagnosed AD cases and 10 clinically normal (CN) subjects. The thicknesses of the 3 mm artificial cortical regions for spherical models with noise levels of 2%, 5%, and 10% were measured by the proposed method as 2.953 ± 0.342, 2.953 ± 0.342 and 2.952 ± 0.343 mm, respectively. Thus the mean thicknesses for the entire cerebral lobar region were 3.1 ± 0.4 mm for AD patients and 3.3 ± 0.4 mm for CN subjects, respectively (p < 0.05). The proposed method could be feasible for measuring the 3D cerebral cortical thickness on individual cortical surface voxels as an atrophy feature in AD.展开更多
文摘Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.
基金supported in part by Council of Scientific and Industrial Research(CSIR),IndiaNational Institute of Health,USA
文摘Okadaic acid： Okadaic acid （OKA）, a polyether （C38 fatty acid） toxin, is a potent and selective inhibitor of protein phosphatase, PP1 and protein phosphatase 2A （PP2A）. It is mainly extracted from a black sponge Hallichondria okadaii and has been suggested to play a potent probe for studying the various molecular, cellular, biochemical and mechanism of neurotoxicity. It is known as a selective and potent in- hibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. It has been reported that Alzheimer＇s disease （AD） is a complex multi- factorial neurodegenerative disorder and hyperphosphor- ylated tau protein is a major pathological hallmark of AD. The reduced activity of phosphatases like, PP2A has been implicated in the brain of AD patients. OKA also induced inhibition of protein phosphatases cause neurofibrillary tangles （NFTs） like pathological changes and tau hyperphos- phorylation seen in AD pathology. Our and others reports inferred that OKA induces neurodegeneration along with tau hyperphosphorylation, GSK3β activation, oxidative stress, neuroinflammation and neurotoxicity which are char- acteristic of AD pathology （Figure 1）.
文摘Alzheimer＇s disease（AD）is a fatal progressive neurodegenerative disorder characterized by loss in memory,cognition,and executive function and activities of daily living.AD pathogenesis has been shown to involve loss of neurons and synapses,cholinergic deficits,amyloid-beta protein（Aβ）deposition,tau protein hyperphosphorylation, and neuroinflammation.
基金Hunan Provincial Natural Science Foundation of China(2022JJ40220)Health Commission of Hunan Province(B202303106781)Hunan Administration of Traditional Chinese Medicine(2021192).
文摘Objective To explore the therapeutic effect and mechanism of Bushen Tiansui Decoction(补肾填髓方,BSTSD)and its active component icariin on Alzheimer’s disease(AD).Methods(i)Animal experiments.This study conducted experiments using specific pathogen-free(SPF)grade male C57BL/6J wild-type(WT)mice and APP/PS1 double transgenic mice.The animals were divided into three groups:WT group(WT mice,n=5,receiving distilled wa-ter daily),APP/PS1 group(APP/PS1 double transgenic mice,n=5,receiving distilled water daily),and BSTSD group[APP/PS1 double transgenic mice,n=5,treated with BSTSD suspen-sion at a dosage of 27 g/(kg·d)for 90 d].Cognitive function was assessed using the Morris wa-ter maze(MWM).Post-experiment,hippocampal tissues were collected for analysis of pyra-midal cell and synaptic morphology through hematoxylin-eosin(HE)staining and transmis-sion electron microscopy(TEM).(ii)Cell experiments.The HT-22 cells were divided into con-trol group(untreated),Aβ_(25-35) group(treated with 20μmol/L Aβ_(25-35) for 24 h),icariin group(pre-treated with 20μmol/L icariin for 60 min,followed by 20μmol/L Aβ_(25-35) for an additional 24 h),and icariin+LY294002 group[treated with 20μmol/L icariin and 20μmol/L LY294002(an inhibitor of the phosphoinostitide 3-kinases(PI3K)signaling pathway)for 60 min,then exposed to 20μmol/L Aβ_(25-35) for 24 h],and cell viability was measured.Western blot was used to detect the expression levels of synapse-associated proteins[synaptophysin(SYP)and post-synaptic density-95(PSD-95)]and PI3K signaling pathway associated proteins[phosphorylat-ed(p)-PI3K/PI3K,p-protein kinase B(Akt)/Akt,and p-mechanistic target of rapamycin(mTOR)/mTOR].Results(i)Animal experiments.Compared with APP/PS1 group,BSTSD group showed that escape latency was significantly shortened(P<0.01)and the frequency of crossing the origi-nal platform was significantly increased(P<0.01).Morphological observation showed that pyramidal cells in the hippocampal CA1 region were arranged more regularly,nuclear stain-ing was uniform,and vacuole-like changes were reduced after BSTSD treatment.TEM showed that the length of synaptic active zone in BSTSD treatment group was increased com-pared with APP/PS1 group(P<0.01),and the width of synaptic gap was decreased(P<0.01).(ii)Cell experiments.Icariin had no obvious toxicity to HT-22 cells when the concentration was not more than 20μmol/L(P>0.05),and alleviated the cell viability decline induced by Aβ_(25-35)(P<0.01).Western blot results showed that compared with Aβ_(25-35) group,the ratios of p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR in icariin group were significantly increased(P<0.01),while the protein expression levels of SYP and PSD-95 were increased(P<0.01).These effects were blocked by LY294002(P<0.01).Conclusion BSTSD and icariin enhance cognitive function and synaptic integrity in AD mod-els and provide potential therapeutic strategies through activation of the PI3K/Akt/mTOR pathway.
文摘Our purpose in this study was to develop an automated method for measuring three-dimensional (3D) cerebral cortical thicknesses in patients with Alzheimer’s disease (AD) using magnetic resonance (MR) images. Our proposed method consists of mainly three steps. First, a brain parenchymal region was segmented based on brain model matching. Second, a 3D fuzzy membership map for a cerebral cortical region was created by applying a fuzzy c-means (FCM) clustering algorithm to T1-weighted MR images. Third, cerebral cortical thickness was three- dimensionally measured on each cortical surface voxel by using a localized gradient vector trajectory in a fuzzy membership map. Spherical models with 3 mm artificial cortical regions, which were produced using three noise levels of 2%, 5%, and 10%, were employed to evaluate the proposed method. We also applied the proposed method to T1-weighted images obtained from 20 cases, i.e., 10 clinically diagnosed AD cases and 10 clinically normal (CN) subjects. The thicknesses of the 3 mm artificial cortical regions for spherical models with noise levels of 2%, 5%, and 10% were measured by the proposed method as 2.953 ± 0.342, 2.953 ± 0.342 and 2.952 ± 0.343 mm, respectively. Thus the mean thicknesses for the entire cerebral lobar region were 3.1 ± 0.4 mm for AD patients and 3.3 ± 0.4 mm for CN subjects, respectively (p < 0.05). The proposed method could be feasible for measuring the 3D cerebral cortical thickness on individual cortical surface voxels as an atrophy feature in AD.
