Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates
Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates
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DOI：
10.1111/j.1471-4159.2008.05295.x
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Schneider, Jay S.
中科院分区：
文献类型：
--
作者：
Guilarte, Tomas R.;Burton, Neal C.;Schneider, Jay S.
长期接触锰 (Mn) 会产生具有精神、认知和帕金森病特征的神经综合征。连续 10 个月每周接受 3.3-5.0 mg Mn/kg 的食蟹猴额叶皮层的基因表达谱显示，与对照组相比，总共 6766 个基因中有 61 个基因增加，4 个基因减少。基因变化与细胞周期调节、DNA修复、细胞凋亡、泛素蛋白酶体系统、蛋白质折叠、胆固醇稳态、轴突/囊泡运输和炎症有关。淀粉样蛋白-β (A beta) 前体样蛋白 1 是淀粉样蛋白前体蛋白家族的成员，是上调程度最高的基因。免疫组织化学证实淀粉样前体样蛋白 1 蛋白表达增加，并揭示暴露于锰的额叶皮层中存在弥漫性 Aβ 斑块。接触锰的动物的皮质神经元和白质纤维积累了表明正在发生退化的银颗粒。皮质神经元还表现出核肥大、胞质内空泡和凋亡柱头。在接触锰的组织中，神经元细胞质以及神经胶质细胞的细胞核和突起中的 p53 免疫标记增加。总之，长期接触锰会产生细胞应激反应，导致神经退行性变化和额叶皮质中弥漫性 Aβ 斑块。这些变化可以解释先前在这些相同动物中表现出的微妙认知缺陷。
Chronic manganese (Mn) exposure produces a neurological syndrome with psychiatric, cognitive, and parkinsonian features. Gene expression profiling in the frontal cortex of Cynomologous macaques receiving 3.3-5.0 mg Mn/kg weekly for 10 months showed that 61 genes were increased and four genes were decreased relative to controls from a total of 6766 genes. Gene changes were associated with cell cycle regulation, DNA repair, apoptosis, ubiquitin-proteasome system, protein folding, cholesterol homeostasis, axonal/vesicular transport, and inflammation. Amyloid-beta (A beta) precursor-like protein 1, a member of the amyloid precursor protein family, was the most highly up-regulated gene. Immunohistochemistry confirmed increased amyloid precursor-like protein 1 protein expression and revealed the presence of diffuse A beta plaques in Mn-exposed frontal cortex. Cortical neurons and white matter fibers from Mn-exposed animals accumulated silver grains indicative of on-going degeneration. Cortical neurons also exhibited nuclear hypertrophy, intracytoplasmic vacuoles, and apoptosis stigmata. p53 immunolabeling was increased in the cytoplasm of neurons and in the nucleus and processes of glial cells in Mn-exposed tissue. In summary, chronic Mn exposure produces a cellular stress response leading to neurodegenerative changes and diffuse A beta plaques in the frontal cortex. These changes may explain the subtle cognitive deficits previously demonstrated in these same animals.