Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients
Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients
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DOI：
10.1186/s12987-019-0160-7
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发表时间：
2019-12-18
影响因子：
7.3
通讯作者：
Eide, Per Kristian
中科院分区：
文献类型：
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作者：
Hasan-Olive, Md Mahdi;Enger, Rune;Eide, Per Kristian
越来越多的证据表明，淀粉样蛋白β和tau蛋白（HP tau）在痴呆亚型特发性正常压力脑积水（iNPH）患者脑中的积累与代谢废物的血管外清除延迟有关。这些患者的细胞内碎片清除是否也受到影响，需要进行检查。假设，代谢物的细胞外和细胞内清除缺陷可能有助于表征iNPH的神经变性和痴呆。本研究探讨了iNPH是否与神经元和星形胶质细胞中线粒体表型的改变有关。方法应用透射电镜对9例正常人和30例iNPH患者的大脑皮质活检组织进行线粒体亚细胞分布和形态学分析。在REF和iNPH患者的神经元索马体中，我们鉴定了正常、病理和成簇的线粒体、线粒体-内质网接触位点和自噬空泡。我们还区分了正常和病理性线粒体在前和突触后神经末梢，以及在星形胶质细胞endfoot进程对血管。结果iNPH组神经元索马体和突触前、后终末的病理性线粒体比例较高，线粒体聚集增多，内质网与线粒体的接触部位数目改变。iNPH患者的神经元索马中的非融合自噬空泡更丰富，提示细胞清除失败。此外，突触后密度的长度减少，在iNPH，可能与突触活动减少。在星形胶质细胞端足突起中，我们还发现iNPH患者中病理性线粒体的数量、面积和面积分数增加。病理性线粒体的比例与星形胶质细胞增生程度的增加和血管周围水通道蛋白4（AQP 4）表达的减少显著相关，通过光学显微镜免疫组织化学评估。结论我们的结果提供了iNPH患者线粒体病理学和细胞清除受损的证据。结果表明，iNPH是一种神经退行性疾病，与阿尔茨海默病非常相似。
Background A growing body of evidence suggests that the accumulation of amyloid-beta and tau (HP tau) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes. Methods Cortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels. Results We found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry. Conclusion Our results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer's disease.