神经退行性变
炎症
NPC1
肝病
组织蛋白酶D
疾病
尼曼-皮克病,C型
生物
病理
血脑屏障
溶酶体贮存病
医学
免疫学
中枢神经系统
内科学
生物化学
内体
酶
受体
作者
Md. Suhail Alam†,Michelle Getz,Sue Y. Yi,Jeffrey L. Kurkewich,Innocent Safeukui,Kasturi Haldar
标识
DOI:10.1074/jbc.m113.526392
摘要
Early diagnosis of neurological disorders would greatly improve their management and treatment. A major hurdle is that inflammatory products of cerebral disease are not easily detected in blood. Inflammation in multiple organs and heterogeneity in disease present additional challenges in distinguishing the extent to which a blood-based marker reflects disease in brain or other afflicted organs. Murine models of the monogenetic disorder Niemann-Pick Type C present aggressive forms of cerebral and liver inflammatory disease. Microarray analyses previously revealed age-dependent changes in innate immunity transcripts in the mouse brain. We have now validated four putative secretory inflammatory markers that are also elevated in mouse liver. We include limited, first time analysis of human Niemann-Pick Type C liver and cerebellum. Furthermore, we utilized 2-hydroxypropyl-β-cyclodextrin (HPβCD, an emerging therapeutic) administered intraperitoneally in mice, which abrogates inflammatory pathology in the liver but has limited effect on the brain. By analyzing the corresponding effects on inflammatory plasma proteins, we identified cathepsin S as a lead indicator of liver disease. In contrast, lysozyme was a marker of both brain and liver disease. 2-Hydroxypropyl-β-cyclodextrin had no effect on transcripts of neuron-specific 24-hydroxylase, and its product 24(S)-hydroxycholesterol was not a useful indicator in mouse plasma. Our data suggest that dual analysis of levels of the inflammatory markers lysozyme and cathepsin S may enable detection of multiple distinct states of neurodegeneration in plasma. Early diagnosis of neurological disorders would greatly improve their management and treatment. A major hurdle is that inflammatory products of cerebral disease are not easily detected in blood. Inflammation in multiple organs and heterogeneity in disease present additional challenges in distinguishing the extent to which a blood-based marker reflects disease in brain or other afflicted organs. Murine models of the monogenetic disorder Niemann-Pick Type C present aggressive forms of cerebral and liver inflammatory disease. Microarray analyses previously revealed age-dependent changes in innate immunity transcripts in the mouse brain. We have now validated four putative secretory inflammatory markers that are also elevated in mouse liver. We include limited, first time analysis of human Niemann-Pick Type C liver and cerebellum. Furthermore, we utilized 2-hydroxypropyl-β-cyclodextrin (HPβCD, an emerging therapeutic) administered intraperitoneally in mice, which abrogates inflammatory pathology in the liver but has limited effect on the brain. By analyzing the corresponding effects on inflammatory plasma proteins, we identified cathepsin S as a lead indicator of liver disease. In contrast, lysozyme was a marker of both brain and liver disease. 2-Hydroxypropyl-β-cyclodextrin had no effect on transcripts of neuron-specific 24-hydroxylase, and its product 24(S)-hydroxycholesterol was not a useful indicator in mouse plasma. Our data suggest that dual analysis of levels of the inflammatory markers lysozyme and cathepsin S may enable detection of multiple distinct states of neurodegeneration in plasma.
科研通智能强力驱动
Strongly Powered by AbleSci AI