Previous studies have reported that non-human primates and rodents exposed to lead during brain development may become dependent on the deposition of pre-determined β-amyloid protein (Aβ),and exhibit upregulation ...Previous studies have reported that non-human primates and rodents exposed to lead during brain development may become dependent on the deposition of pre-determined β-amyloid protein (Aβ),and exhibit upregulation of β-site amyloid precursor protein expression in old age.However,further evidence is required to elucidate the precise relationship and molecular mechanisms underlying the effects of early lead exposure on excessive Aβ production in adult mammals.The present study investigated the effects of lead exposure on expression of β-amyloid precursor protein cleavage enzyme-1 (BACE-1) in the rat retina and the production of Aβ in early development,using the retina as a window for studying Alzheimer's disease.Adult rats were intraocularly injected with different doses of lead acetate (10μmol/L,100μmol/L,1 mmol/L,10 mmol/L and 100 mmol/L).The results revealed that retinal lead concentration,BACE-1 and its cleavage products β-C-terminal fragment and retina Aβ1-40 were all significantly increased in almost all of the lead exposure groups 48 hours later in a dose-dependent manner.The only exception was the 10μmol/L group.The distribution of BACE-1 in the retina did not exhibit obvious changes,and no distinctive increase in the activation of retinal microglia was apparent.Similarly,retinal synaptophysin expression did not exhibit any clear changes.These data suggest that lead exposure can result in the upregulation of retinal neuron BACE-1 expression in the early period of development and further increase the overproduction of Aβ1-40 in the retina.Our results provided novel insight into the molecular mechanisms underlying environmentally-induced Alzheimer's disease.展开更多
BACKGROUND: The pharmacological actions of Panax notoginseng saponins (PNS) lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheime...BACKGROUND: The pharmacological actions of Panax notoginseng saponins (PNS) lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheimer's disease. OBJECTIVE: Using the Morris water maze, immunohistochemistry, real-time PCR and RT-PCR, this study aimed to measure improvement in spatial learning, memory, expression of amyloid precursor protein (App) and β -amyloid (A β ), to investigate the mechanism of action of PNS in the treatment of AD in the senescence accelerated mouse-prone 8 (SAMP8) and compare the effects with huperzine A. DESIGN, TIME AND SETTING: A completely randomized grouping design, controlled animal experiment was performed in the Center for Research & Development of New Drugs, Guangxi Traditional Chinese Medical University from July 2005 to April 2007. MATERIALS: Sixty male SAMP8 mice, aged 3 months, purchased from Tianjin Chinese Traditional Medical University of China, were divided into four groups: PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. PNS was provided by Weihe Pharmaceutical Co., Ltd. (batch No.: Z53021485, Yuxi, Yunan Province, China). Huperzine A was provided by Zhenyuan Pharmaceutical Co., Ltd. (batch No.: 20040801, Zhejiang, China). METHODS: The high-dosage group and low-dosage group were treated with 93.50 and 23.38 mg/kg PNS respectively per day and the huperzine A group was treated with 0.038 6 mg/kg huperzine A per day, all by intragastric administration, for 8 consecutive weeks. The same volume of double distilled water was given to the control group. MAIN OUTCOME MEASURES: After drug administration, learning and memory abilities were assessed by place navigation and spatial probe tests. The recording indices consisted of escape latency (time-to-platform), and the percentage of swimming time spent in each quadrant. The number of A β 1-40, A β 1-42 and App immunopositive neurons in the brains of SAMP8 mice was analyzed by immunohistochemistry. The mRNA content ofApp, tau, acetylcholinesterase, and synaptophysin (Syp) was tested by real time PCR and RT-PCR. RESULTS: The PCR results show that PNS can downregulate the expression of the App gene and upregulate the expression of the Syp gene in the parietal cortex and hippocampus of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than those of the PNS low-dosage group and the huperzine A group (P 〈 0.05). The results of the Morris water maze and immunohistochemistry indicated that PNS can improve the capacity for spatial learning and memory in SAMP8 mice, and reduce the content of A β 1-40, A β 1-42 and expression of App in the brains of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than that of the PNS low-dosage group and the huperzine A group (P 〈 0.05). CONCLUSION: These results support the hypothesis that PNS plays a therapeutic and protective role on the pathological lesions and learning dysfunction of Alzheimer's disease. The therapeutic effects of PNS for Alzheimer's disease are possibly achieved through downregulating the expression of the App gene and upregulating the expression of the Syp gene. The therapeutic effects of PNS are dose-dependent and are greater than the effect of huperzine A.展开更多
Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives.While the etiology of AD remain...Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives.While the etiology of AD remains an enigma,excessive accumulation ofβ-amyloid peptide(Aβ)is widely believed to induce pathological changes and cause dementia in brains of AD patients.BACE1 was discovered to initiate the cleavage of amyloid precursor protein(APP)at theβ-secretase site.Only after this cleavage doesγ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ.Hence,blocking BACE1 proteolytic activity will suppress Aβgeneration.Due to the linkage of Aβto the potential cause of AD,extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy.With the recent breakthrough in developing brain-penetrable BACE1 inhibitors,targeting amyloid deposition-mediated pathology for AD therapy has now become more practical.This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs,such as MK8931,AZD-3293,JNJ-54861911,E2609 and CNP520.These drugs are currently in clinical trials and their updated states will be discussed.With the promise of reducing Aβgeneration and deposition with no alarming safety concerns,the amyloid cascade hypothesis in AD therapy may finally become validated.展开更多
基金the National Natural Science Foundation of China,No.30900773the National University Basic Research Foundation of China,No.2010QZZD022
文摘Previous studies have reported that non-human primates and rodents exposed to lead during brain development may become dependent on the deposition of pre-determined β-amyloid protein (Aβ),and exhibit upregulation of β-site amyloid precursor protein expression in old age.However,further evidence is required to elucidate the precise relationship and molecular mechanisms underlying the effects of early lead exposure on excessive Aβ production in adult mammals.The present study investigated the effects of lead exposure on expression of β-amyloid precursor protein cleavage enzyme-1 (BACE-1) in the rat retina and the production of Aβ in early development,using the retina as a window for studying Alzheimer's disease.Adult rats were intraocularly injected with different doses of lead acetate (10μmol/L,100μmol/L,1 mmol/L,10 mmol/L and 100 mmol/L).The results revealed that retinal lead concentration,BACE-1 and its cleavage products β-C-terminal fragment and retina Aβ1-40 were all significantly increased in almost all of the lead exposure groups 48 hours later in a dose-dependent manner.The only exception was the 10μmol/L group.The distribution of BACE-1 in the retina did not exhibit obvious changes,and no distinctive increase in the activation of retinal microglia was apparent.Similarly,retinal synaptophysin expression did not exhibit any clear changes.These data suggest that lead exposure can result in the upregulation of retinal neuron BACE-1 expression in the early period of development and further increase the overproduction of Aβ1-40 in the retina.Our results provided novel insight into the molecular mechanisms underlying environmentally-induced Alzheimer's disease.
基金the National Natural Science Foundation of China, No: 30560189
文摘BACKGROUND: The pharmacological actions of Panax notoginseng saponins (PNS) lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheimer's disease. OBJECTIVE: Using the Morris water maze, immunohistochemistry, real-time PCR and RT-PCR, this study aimed to measure improvement in spatial learning, memory, expression of amyloid precursor protein (App) and β -amyloid (A β ), to investigate the mechanism of action of PNS in the treatment of AD in the senescence accelerated mouse-prone 8 (SAMP8) and compare the effects with huperzine A. DESIGN, TIME AND SETTING: A completely randomized grouping design, controlled animal experiment was performed in the Center for Research & Development of New Drugs, Guangxi Traditional Chinese Medical University from July 2005 to April 2007. MATERIALS: Sixty male SAMP8 mice, aged 3 months, purchased from Tianjin Chinese Traditional Medical University of China, were divided into four groups: PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. PNS was provided by Weihe Pharmaceutical Co., Ltd. (batch No.: Z53021485, Yuxi, Yunan Province, China). Huperzine A was provided by Zhenyuan Pharmaceutical Co., Ltd. (batch No.: 20040801, Zhejiang, China). METHODS: The high-dosage group and low-dosage group were treated with 93.50 and 23.38 mg/kg PNS respectively per day and the huperzine A group was treated with 0.038 6 mg/kg huperzine A per day, all by intragastric administration, for 8 consecutive weeks. The same volume of double distilled water was given to the control group. MAIN OUTCOME MEASURES: After drug administration, learning and memory abilities were assessed by place navigation and spatial probe tests. The recording indices consisted of escape latency (time-to-platform), and the percentage of swimming time spent in each quadrant. The number of A β 1-40, A β 1-42 and App immunopositive neurons in the brains of SAMP8 mice was analyzed by immunohistochemistry. The mRNA content ofApp, tau, acetylcholinesterase, and synaptophysin (Syp) was tested by real time PCR and RT-PCR. RESULTS: The PCR results show that PNS can downregulate the expression of the App gene and upregulate the expression of the Syp gene in the parietal cortex and hippocampus of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than those of the PNS low-dosage group and the huperzine A group (P 〈 0.05). The results of the Morris water maze and immunohistochemistry indicated that PNS can improve the capacity for spatial learning and memory in SAMP8 mice, and reduce the content of A β 1-40, A β 1-42 and expression of App in the brains of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than that of the PNS low-dosage group and the huperzine A group (P 〈 0.05). CONCLUSION: These results support the hypothesis that PNS plays a therapeutic and protective role on the pathological lesions and learning dysfunction of Alzheimer's disease. The therapeutic effects of PNS for Alzheimer's disease are possibly achieved through downregulating the expression of the App gene and upregulating the expression of the Syp gene. The therapeutic effects of PNS are dose-dependent and are greater than the effect of huperzine A.
基金R Yan is supported by the grant(AG025493,MH103942,NS074256 and AG046929)from the National Institutes of Health.
文摘Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives.While the etiology of AD remains an enigma,excessive accumulation ofβ-amyloid peptide(Aβ)is widely believed to induce pathological changes and cause dementia in brains of AD patients.BACE1 was discovered to initiate the cleavage of amyloid precursor protein(APP)at theβ-secretase site.Only after this cleavage doesγ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ.Hence,blocking BACE1 proteolytic activity will suppress Aβgeneration.Due to the linkage of Aβto the potential cause of AD,extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy.With the recent breakthrough in developing brain-penetrable BACE1 inhibitors,targeting amyloid deposition-mediated pathology for AD therapy has now become more practical.This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs,such as MK8931,AZD-3293,JNJ-54861911,E2609 and CNP520.These drugs are currently in clinical trials and their updated states will be discussed.With the promise of reducing Aβgeneration and deposition with no alarming safety concerns,the amyloid cascade hypothesis in AD therapy may finally become validated.