Reynolds W F, Rhees J, Maciejewski D, Paladino T, Sieburg H, Maki R A, Masliah E
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, California, 92121, USA.
Exp Neurol. 1999 Jan;155(1):31-41. doi: 10.1006/exnr.1998.6977.
Myeloperoxidase (MPO) is a myeloid-specific enzyme that generates hypochlorous acid and other reactive oxygen species. MPO is present at high levels in circulating neutrophils and monocytes but is not detectable in microglia, brain-specific macrophages, in normal brain tissue. However, an earlier study indicated that MPO is present in macrophage-microglia at multiple sclerosis lesions, suggesting that reactivation of MPO gene expression may play a role in neurodegenerative diseases involving macrophage-microglia. In the present study, MPO is shown to colocalize with amyloid beta (Abeta) in senile plaques in cerebral cortex sections from Alzheimer's disease (AD) brain tissue. Microglia costaining for MPO and CD68 are closely associated with plaques, suggesting that plaque components induce MPO expression in microglia. In support of this interpretation, treatment of rodent microglia with aggregated Abeta(1-42) was shown to induce MPO mRNA expression. Also, the ApoE4 allele, the major AD risk factor associated with increased Abeta deposition, was shown to correlate with increased MPO deposition in plaques (P = 0.01, ANOVA). Finally, a genetic polymorphism links MPO expression to Alzheimer's risk, in that a higher expressing SpSp MPO genotype was associated with increased incidence of AD in females, and decreased incidence in males (P = 0.006). These findings suggest that the MPO polymorphism is a gender-specific risk factor for Alzheimer's disease.
髓过氧化物酶（MPO）是一种髓系特异性酶，可产生次氯酸和其他活性氧物质。MPO在循环中的中性粒细胞和单核细胞中含量很高，但在正常脑组织中的小胶质细胞（脑特异性巨噬细胞）中无法检测到。然而，一项早期研究表明，MPO存在于多发性硬化症病变中的巨噬细胞-小胶质细胞中，这表明MPO基因表达的重新激活可能在涉及巨噬细胞-小胶质细胞的神经退行性疾病中起作用。在本研究中，MPO显示与阿尔茨海默病（AD）脑组织皮质切片老年斑中的β淀粉样蛋白（Aβ）共定位。MPO和CD68的小胶质细胞共染色与斑块密切相关，表明斑块成分可诱导小胶质细胞中MPO的表达。支持这一解释的是，用聚集的Aβ（1-42）处理啮齿动物小胶质细胞可诱导MPO mRNA表达。此外，ApoE4等位基因是与Aβ沉积增加相关的主要AD风险因素，它与斑块中MPO沉积增加相关（方差分析，P = 0.01）。最后，一种基因多态性将MPO表达与患阿尔茨海默病的风险联系起来，即高表达的SpSp MPO基因型与女性AD发病率增加相关，而与男性发病率降低相关（P = 0.006）。这些发现表明，MPO多态性是阿尔茨海默病的一种性别特异性风险因素。
