Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-assoc...Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain unclear.Methods:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice.Changes in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were examined.In addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.Results:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive impairments.These mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex.Furthermore,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis.Abnormal expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also observed.Conclusion:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice.The mechanism may involve the induction of central and peripheral lipid metabolism disorders.Therefore,modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression.This study also provided a better animal model for studying AD comorbid with depression.展开更多
Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have ...Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have shown that the expression of ACE2 in AD is reduced,but its role in AD is still unclear.Method:We induced AD damage in endothelial cells using Aβ25-35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection.We detected the effect of Aβ25-35 on cell viability using the CCK-8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay.We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway,tight junction protein,and NF-κB pathway.Results:Aβ25-35 treatment significantly decreased the expression of ACE2 and reduced cell viability.ACE2 overexpression(1)reduced the number of branches and junctions in tube formation,(2)inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25-35,(3)increased the expression of TJPs,including ZO-1 and claudin-5,and(4)restored Aβ25-35-induced activation of the NF-κB pathway.Conclusion:Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF-κB/VEGF/VEGFR2 pathway activity.ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.展开更多
Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autops...Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates(NHPs)models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients.Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans.Minor and limited phenotypic and histopathological changes were observed in adult models.Systemic proteomics and metabolomics results indicated metabolic disorders,mainly enriched in insulin resistance pathways,in infected adult NHPs,along with elevated fasting C-peptide and C-peptide/glucose ratio levels.Furthermore,in elder COVID-19 NHPs,SARS-CoV-2 infection causes loss of beta(β)cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis,activation ofα-SMA and aggravated fibrosis consisting of lower collagen in serum,an increase of pancreatic inflammation and stress markers,ICAM-1 and G3BP1,along with more severe glycometabolic dysfunction.In contrast,vaccination maintained glucose homeostasis by activating insulin receptorαand insulin receptorβ.Overall,the cumulative risk of diabetes post-COVID-19 is closely tied to age,suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.展开更多
Wen-Yi refers to an acute infectious disease that is highly contagious and can cause widespread epidemics.Also known as“Yi”or“Li”in the Chinese medicine(CM)literature,Wen-Yi diseases,such as corona virus disease 2...Wen-Yi refers to an acute infectious disease that is highly contagious and can cause widespread epidemics.Also known as“Yi”or“Li”in the Chinese medicine(CM)literature,Wen-Yi diseases,such as corona virus disease 2019(COVID-19),seasonal influenza,malaria,and tuberculosis,have imposed a significant disease burden globally.展开更多
The number of genetically modified mouse models that mimic human disease is growing rapidly,but only a tiny fraction has been commonly used.According to The Knockout Mouse Program(Lloyd,2011),a public resource of mous...The number of genetically modified mouse models that mimic human disease is growing rapidly,but only a tiny fraction has been commonly used.According to The Knockout Mouse Program(Lloyd,2011),a public resource of mouse embryonic stem cells containing a null mutation in every gene in the mouse genome,8,916 mutant mice lines were phenotyped up to 19 July 2022.Due to the poor correlation between the genomic responses in the mouse models and those responses in human disease,and since humans differ significantly in their genetic vulnerability to common diseases,we still need better mouse models,especially for common and chronic human diseases,including cancer,pulmonary and cardiovascular diseases,obesity and diabetes,behavioral disorders,and neurodegenerative diseases.These new models will be placed into a public repository,The China National Human Disease Animal Model Resource Center(NAMR).This project is funded by Ministry of Science and Technology of China and specializes in the creation,introduction,collection,preservation,and supply of animal model resources forhuman diseases.展开更多
基金CAMS initiative for Innovative Medicine of China,Grant/Award Number:2021-I2M-1-034。
文摘Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain unclear.Methods:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice.Changes in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were examined.In addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.Results:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive impairments.These mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex.Furthermore,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis.Abnormal expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also observed.Conclusion:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice.The mechanism may involve the induction of central and peripheral lipid metabolism disorders.Therefore,modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression.This study also provided a better animal model for studying AD comorbid with depression.
基金Peking Union Medical CollegeCAMS initiative for Innovative Medicine of ChinaGrant/Award Number:2021-I2M-1-034
文摘Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have shown that the expression of ACE2 in AD is reduced,but its role in AD is still unclear.Method:We induced AD damage in endothelial cells using Aβ25-35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection.We detected the effect of Aβ25-35 on cell viability using the CCK-8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay.We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway,tight junction protein,and NF-κB pathway.Results:Aβ25-35 treatment significantly decreased the expression of ACE2 and reduced cell viability.ACE2 overexpression(1)reduced the number of branches and junctions in tube formation,(2)inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25-35,(3)increased the expression of TJPs,including ZO-1 and claudin-5,and(4)restored Aβ25-35-induced activation of the NF-κB pathway.Conclusion:Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF-κB/VEGF/VEGFR2 pathway activity.ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.
基金supported by the Institute of Basic Medical Sciences,the Chinese Academy of Medical Sciences,the Neuroscience Center,the China Human Brain Banking Consortium,the ALS Brain Bank Initiative in China,and Home for Heal and Help for their assistance in this paper.This work was supported by the National Natural Science Foundation of China(82141204,82061138007,82221004,82041008)the National Key Research and Development Project of China(2020YFA0707803)+2 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)grant(2021-1-I2M-035,2021-1-I2M-034 and 2021-CAMS-JZ002)Bill&Melinda Gates Foundation(INV-006371)Key-Area Research and Development Program of Guangdong Province(2022B1111020005).
文摘Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates(NHPs)models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients.Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans.Minor and limited phenotypic and histopathological changes were observed in adult models.Systemic proteomics and metabolomics results indicated metabolic disorders,mainly enriched in insulin resistance pathways,in infected adult NHPs,along with elevated fasting C-peptide and C-peptide/glucose ratio levels.Furthermore,in elder COVID-19 NHPs,SARS-CoV-2 infection causes loss of beta(β)cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis,activation ofα-SMA and aggravated fibrosis consisting of lower collagen in serum,an increase of pancreatic inflammation and stress markers,ICAM-1 and G3BP1,along with more severe glycometabolic dysfunction.In contrast,vaccination maintained glucose homeostasis by activating insulin receptorαand insulin receptorβ.Overall,the cumulative risk of diabetes post-COVID-19 is closely tied to age,suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.
基金supported by the China Academy of Chinese Medical Sciences Fund(2023007,ZZ17-YQ-036,z0849,z0832)the National Natural Science Foundation of China(82061138007,82274350)+1 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-I2M-035,2021-1-I2M-034,2021-CAMSJZ002)Guangdong Key Research and Development Project(2022B1111020005)。
文摘Wen-Yi refers to an acute infectious disease that is highly contagious and can cause widespread epidemics.Also known as“Yi”or“Li”in the Chinese medicine(CM)literature,Wen-Yi diseases,such as corona virus disease 2019(COVID-19),seasonal influenza,malaria,and tuberculosis,have imposed a significant disease burden globally.
基金supported by grants from CAMS initiative for Innovative Medicine of China(No.2021-I2M-1-034)National Key R&D Program of China(No.2021YFF0703200)National Natural Science Foundation of China(No.82041008 and 82161138027).
文摘The number of genetically modified mouse models that mimic human disease is growing rapidly,but only a tiny fraction has been commonly used.According to The Knockout Mouse Program(Lloyd,2011),a public resource of mouse embryonic stem cells containing a null mutation in every gene in the mouse genome,8,916 mutant mice lines were phenotyped up to 19 July 2022.Due to the poor correlation between the genomic responses in the mouse models and those responses in human disease,and since humans differ significantly in their genetic vulnerability to common diseases,we still need better mouse models,especially for common and chronic human diseases,including cancer,pulmonary and cardiovascular diseases,obesity and diabetes,behavioral disorders,and neurodegenerative diseases.These new models will be placed into a public repository,The China National Human Disease Animal Model Resource Center(NAMR).This project is funded by Ministry of Science and Technology of China and specializes in the creation,introduction,collection,preservation,and supply of animal model resources forhuman diseases.
