目的:探讨IL-34对ApoE-/-小鼠动脉粥样硬化(AS)和炎症反应的影响。方法:给予高脂饲料喂养的雄性ApoE-/-小鼠20只分为两组,每组10只。实验组隔天1次腹腔注射200 ng重组IL-34(rIL-34),对照组隔天1次腹腔注射0.3 mL PBS,干预12周。检测小...目的:探讨IL-34对ApoE-/-小鼠动脉粥样硬化(AS)和炎症反应的影响。方法:给予高脂饲料喂养的雄性ApoE-/-小鼠20只分为两组,每组10只。实验组隔天1次腹腔注射200 ng重组IL-34(rIL-34),对照组隔天1次腹腔注射0.3 mL PBS,干预12周。检测小鼠血清总胆固醇(TC),甘油三酯(TG)及高密度脂蛋白胆固醇(HDL-C);油红O染色评估小鼠主动脉AS形成情况;免疫组化法检测主动脉根部斑块炎症细胞(CD3+T细胞和Mac-3+巨噬细胞)浸润情况;流式细胞术检测脾脏T细胞亚群;ELISA法和Bio-Plex系统检测小鼠血清细胞炎性因子IL-1β、TNF-α、IFN-γ、IL-6、IL-4、IL-10、TGF-β1和IL-17A水平;qRT-PCR法检测小鼠主动脉弓上述细胞因子mRNA的表达水平。结果:两组小鼠血脂水平差异无统计学意义(P>0.05))。与对照组比较,实验组小鼠血清IL-34水平增加,主动脉和主动脉根部斑块面积增加,斑块内CD3+T细胞和Mac-3+巨噬细胞浸润增多,脾脏Th17细胞亚群比例升高,血清IL-1β、TNF-α、IFN-γ、IL-6和IL-17A水平升高,主动脉弓IL-1β、TNF-α、IFN-γ、IL-6和IL-17A mRNA表达水平升高(P均<0.05)。结论:IL-34可升高脾脏Th17细胞亚群比例,促进炎症因子表达,有助于小鼠AS形成。展开更多
Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic ...Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.展开更多
文摘目的:探讨IL-34对ApoE-/-小鼠动脉粥样硬化(AS)和炎症反应的影响。方法:给予高脂饲料喂养的雄性ApoE-/-小鼠20只分为两组,每组10只。实验组隔天1次腹腔注射200 ng重组IL-34(rIL-34),对照组隔天1次腹腔注射0.3 mL PBS,干预12周。检测小鼠血清总胆固醇(TC),甘油三酯(TG)及高密度脂蛋白胆固醇(HDL-C);油红O染色评估小鼠主动脉AS形成情况;免疫组化法检测主动脉根部斑块炎症细胞(CD3+T细胞和Mac-3+巨噬细胞)浸润情况;流式细胞术检测脾脏T细胞亚群;ELISA法和Bio-Plex系统检测小鼠血清细胞炎性因子IL-1β、TNF-α、IFN-γ、IL-6、IL-4、IL-10、TGF-β1和IL-17A水平;qRT-PCR法检测小鼠主动脉弓上述细胞因子mRNA的表达水平。结果:两组小鼠血脂水平差异无统计学意义(P>0.05))。与对照组比较,实验组小鼠血清IL-34水平增加,主动脉和主动脉根部斑块面积增加,斑块内CD3+T细胞和Mac-3+巨噬细胞浸润增多,脾脏Th17细胞亚群比例升高,血清IL-1β、TNF-α、IFN-γ、IL-6和IL-17A水平升高,主动脉弓IL-1β、TNF-α、IFN-γ、IL-6和IL-17A mRNA表达水平升高(P均<0.05)。结论:IL-34可升高脾脏Th17细胞亚群比例,促进炎症因子表达,有助于小鼠AS形成。
文摘Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E(APOE) genotypes and their corresponding protein(Apo E) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes(APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among Apo E, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of Apo E's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides Apo E-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease(depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.
