OBJECTIVE To investigate the effect of LW-AFC,a new formula of the main active components extracted fromLiuwei Dihuang decoction,on treatment of Alzheimer disease(AD) in mouse models.METHODS After treatment LW-AFC,mic...OBJECTIVE To investigate the effect of LW-AFC,a new formula of the main active components extracted fromLiuwei Dihuang decoction,on treatment of Alzheimer disease(AD) in mouse models.METHODS After treatment LW-AFC,mice were cognitively evaluated in behavioral experiments.Neuron loss,amyloid-β(Αβ) deposition,and Αβ level were analyzed using Nissl staining,immunofluorescence,and an Alpha LISA assay,respectively.Multiplex bead analysis,a radioimmunoassay,immunochemiluminometry,and an ELISA were used to measure cytokine and hormone levels.Lymphocyte subsets were detected using flow cytometry.RESULTS LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice,including the impairment of object recognition memory,spatial learning and memory,and active and passive avoidance.In addition,LW-AFC alleviated the neuron loss in the hippocampus,suppressed Αβ deposition in the brain,and reduced the concentration of Aβ1-42 in the hippocampus and plasma of APP/PS1 mice.LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus,and adrenocorticotropic hormone,luteinizing hormone,and follicle-stimulating hormone in the pituitary.Moreover,LW-AFC increased CD8+CD28+T cells,and reduced CD4^+CD25^+Foxp3^+T cells in the spleen lymphocytes,down-regulated interleukin(IL)-1β,IL-2,IL-6,IL-23,granulocyte-macrophage colony stimulating factor,and tumor necrosis factor-α and-β,and up-regulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice.CONCLUSION LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic micevia the restoration of the NIM network to a greater extent than either memantineor donepezil,which supports the use of LW-AFC as a potential agent for AD therapy.展开更多
OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progressio...OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in amyloid precursor protein/presenilin 1(APP/PS1) transgenic mice. METHODS The upregulation of cerebral Klotho expression was mediated by intracerebroventricular administration of a lentiviral vector that encoded Klotho(LV-KL) in APP/PS1 transgenicmice.RESULTS LV-KL significantly increased Klotho overexpression and effectively ameliorated cognitive deficits and AD-like pathology in aged AD mice. LV-KL might induce autophagy activation and protein kinase B/mammalian target of rapamycin inhibition in both AD mice and cultured BV2 murine microglia. Meanwhile, LV-KL altered the expression of low density lipoprotein receptor-related protein 1(LRP-1), receptor for advanced glycation end products, P-glycoprotein and ABCA1 both at the brain microvascular and choroid plexus as well as the contents of plasma s LRP-1 in aged AD mice.CONCLUSION The current results indicate that Klotho plays a crucial role in the clearance of cerebral amyloid β protein and the progression of AD in mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.展开更多
OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHOD...OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5 Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology.APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits.APP/PS1 transgenic mice were randomly placed into three groups(n=10):The two 6-month transgenic groups were administrated with 30 mg·kg^(-1) DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec.tion.After 100-day administration,nest construction assay and Morris water maze(MWM) assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment.Upon completion of behavior assays,mice were euthanized,and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde.RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice,and the underlying mechanisms have been inten.sively investigated.DDPU reduced Ab production by inhibiting the PERK/eIF2 a signaling-mediated BACE1 translation,while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress.Therefore,all findings have clearly demonstrated the crosstalk between Ab and ER stress,and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.展开更多
基金supported by National Science and Technology Major Projects Initiative(2013ZX09508104)National Natural Science Foundation of China(81473191)
文摘OBJECTIVE To investigate the effect of LW-AFC,a new formula of the main active components extracted fromLiuwei Dihuang decoction,on treatment of Alzheimer disease(AD) in mouse models.METHODS After treatment LW-AFC,mice were cognitively evaluated in behavioral experiments.Neuron loss,amyloid-β(Αβ) deposition,and Αβ level were analyzed using Nissl staining,immunofluorescence,and an Alpha LISA assay,respectively.Multiplex bead analysis,a radioimmunoassay,immunochemiluminometry,and an ELISA were used to measure cytokine and hormone levels.Lymphocyte subsets were detected using flow cytometry.RESULTS LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice,including the impairment of object recognition memory,spatial learning and memory,and active and passive avoidance.In addition,LW-AFC alleviated the neuron loss in the hippocampus,suppressed Αβ deposition in the brain,and reduced the concentration of Aβ1-42 in the hippocampus and plasma of APP/PS1 mice.LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus,and adrenocorticotropic hormone,luteinizing hormone,and follicle-stimulating hormone in the pituitary.Moreover,LW-AFC increased CD8+CD28+T cells,and reduced CD4^+CD25^+Foxp3^+T cells in the spleen lymphocytes,down-regulated interleukin(IL)-1β,IL-2,IL-6,IL-23,granulocyte-macrophage colony stimulating factor,and tumor necrosis factor-α and-β,and up-regulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice.CONCLUSION LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic micevia the restoration of the NIM network to a greater extent than either memantineor donepezil,which supports the use of LW-AFC as a potential agent for AD therapy.
文摘OBJECTIVE Alzheimer disease(AD) is the most common type of senile dementia. The anti-aging gene Klotho is reported to decline in the brain of patients and animals with AD. However, the role of Klotho in the progression of AD remains elusive. The present study explored the effects and underlying mechanism of Klotho in amyloid precursor protein/presenilin 1(APP/PS1) transgenic mice. METHODS The upregulation of cerebral Klotho expression was mediated by intracerebroventricular administration of a lentiviral vector that encoded Klotho(LV-KL) in APP/PS1 transgenicmice.RESULTS LV-KL significantly increased Klotho overexpression and effectively ameliorated cognitive deficits and AD-like pathology in aged AD mice. LV-KL might induce autophagy activation and protein kinase B/mammalian target of rapamycin inhibition in both AD mice and cultured BV2 murine microglia. Meanwhile, LV-KL altered the expression of low density lipoprotein receptor-related protein 1(LRP-1), receptor for advanced glycation end products, P-glycoprotein and ABCA1 both at the brain microvascular and choroid plexus as well as the contents of plasma s LRP-1 in aged AD mice.CONCLUSION The current results indicate that Klotho plays a crucial role in the clearance of cerebral amyloid β protein and the progression of AD in mice. These findings highlight the preventive and therapeutic potential of Klotho for the treatment of AD.
基金supported by National Natural Science Foundation of China(81220108025,81473141) NSFC-TRF collaboration projects(81561148011,DBG5980001)+3 种基金 Drug Innovation Project of SIMM(CASIMM0120154035) Personalized Medicine-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of Chinese Academy of Sciences (XDA12040303) the Project Funded by the Priority Aca-demic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medi-cine17KJA350002) National Natural Science Foundation for Young Scientists of China (81703806)
文摘OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5 Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology.APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits.APP/PS1 transgenic mice were randomly placed into three groups(n=10):The two 6-month transgenic groups were administrated with 30 mg·kg^(-1) DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec.tion.After 100-day administration,nest construction assay and Morris water maze(MWM) assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment.Upon completion of behavior assays,mice were euthanized,and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde.RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice,and the underlying mechanisms have been inten.sively investigated.DDPU reduced Ab production by inhibiting the PERK/eIF2 a signaling-mediated BACE1 translation,while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress.Therefore,all findings have clearly demonstrated the crosstalk between Ab and ER stress,and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.
