Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
J Neuroinflammation. 2019 Feb 25;16(1):48. doi: 10.1186/s12974-019-1436-1.
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and frontotemporal lobar dementia (FTLD) are characterized by progressive neuronal loss but differ in their underlying pathological mechanisms. However, neuroinflammation is commonly observed within these different forms of dementia. Recently, it has been suggested that an altered sphingolipid metabolism may contribute to the pathogenesis of a variety of neurodegenerative conditions. Especially ceramide, the precursor of all complex sphingolipids, is thought to be associated with pro-apoptotic cellular processes, thereby propagating neurodegeneration and neuroinflammation, although it remains unclear to what extent. The current pathological study therefore investigates whether increased levels of ceramide are associated with the degree of neuroinflammation in various neurodegenerative disorders.
Immunohistochemistry was performed on human post-mortem tissue of PDD and FTLD Pick's disease cases, which are well-characterized cases of dementia subtypes differing in their neuroinflammatory status, to assess the expression and localization of ceramide, acid sphingomyelinase, and ceramide synthase 2 and 5. In addition, we determined the concentration of sphingosine, sphingosine-1-phosphate (S1P), and ceramide species differing in their chain-length in brain homogenates of the post-mortem tissue using HPLC-MS/MS.
Our immunohistochemical analysis reveals that neuroinflammation is associated with increased ceramide levels in astrocytes in FTLD Pick's disease. Moreover, the observed increase in ceramide in astrocytes correlates with the expression of ceramide synthase 5. In addition, HPLC-MS/MS analysis shows a shift in ceramide species under neuroinflammatory conditions, favoring pro-apoptotic ceramide.
Together, these findings suggest that detected increased levels of pro-apoptotic ceramide might be a common denominator of neuroinflammation in different neurodegenerative diseases.
神经退行性疾病，如阿尔茨海默病（AD）、帕金森病痴呆（PDD）和额颞叶痴呆（FTLD），其特征是神经元进行性丧失，但在其潜在的病理机制上有所不同。然而，神经炎症在这些不同形式的痴呆中普遍存在。最近，有人提出，鞘脂代谢的改变可能有助于多种神经退行性疾病的发病机制。特别是神经酰胺，所有复杂鞘脂的前体，被认为与促凋亡的细胞过程有关，从而导致神经退行性变和神经炎症，尽管其程度尚不清楚。因此，目前的病理研究调查了神经酰胺水平的升高是否与各种神经退行性疾病中神经炎症的程度有关。
对 PDD 和 FTLD Pick 病病例的人类死后组织进行免疫组织化学染色，这些病例是神经炎症状态不同的痴呆亚型的典型病例，以评估神经酰胺、酸性鞘磷脂酶和神经酰胺合酶 2 和 5 的表达和定位。此外，我们使用 HPLC-MS/MS 测定死后组织脑匀浆中鞘氨醇、鞘氨醇-1-磷酸（S1P）和链长不同的神经酰胺的浓度。
我们的免疫组织化学分析表明，FTLD Pick 病中的神经炎症与星形胶质细胞中神经酰胺水平的升高有关。此外，星形胶质细胞中观察到的神经酰胺增加与神经酰胺合酶 5 的表达相关。此外，HPLC-MS/MS 分析显示在神经炎症条件下神经酰胺的种类发生变化，有利于促凋亡的神经酰胺。
综上所述，这些发现表明，检测到的促凋亡神经酰胺水平升高可能是不同神经退行性疾病中神经炎症的共同特征。
