Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32610, USA.
Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32610, USA.
Brain Behav Immun. 2016 Jul;55:191-201. doi: 10.1016/j.bbi.2015.10.012. Epub 2015 Oct 27.
Microglial activation (neuroinflammation) is often cited as a pathogenic factor in the development of neurodegenerative diseases. However, there are significant caveats associated with the idea that inflammation directly causes either α-synuclein pathology or neurofibrillary degeneration (NFD). We have performed immunohistochemical studies on microglial cells in five cases of dementia with Lewy bodies (DLB), median age 87, and nine cases of non-demented (ND) controls, median age 74, using tissue samples from the temporal lobe and the superior frontal gyrus. Three different antibodies known to label microglia and macrophages were employed: iba1, anti-CD68, and anti-ferritin. All DLB cases showed both α-synuclein pathology (Lewy bodies and neurites) and NFD ranging from Braak stage II to IV. In contrast, all controls were devoid of α-synuclein pathology but did show NFD ranging from Braak stage I to III. Using iba1 labeling, our current results show a notable absence of activated microglia in all cases with the exception of two controls that showed small focal areas of microglial activation and macrophage formation. Both iba1 and ferritin antibodies revealed a mixture of ramified and dystrophic microglial cells throughout the regions examined, and there were no measurable differences in the prevalence of dystrophic microglial cells between DLB and controls. Double-labeling for α-synuclein and iba1-positive microglia showed that cortical Lewy bodies were surrounded by both ramified and dystrophic microglial cells. We found an increase in CD68 expression in DLB cases relative to controls. Since microglial dystrophy has been linked to NFD and since it did not appear to be worse in DLB cases over controls, our findings support the idea that the additional Lewy body pathology in DLB is not the result of intensified microglial dystrophy. CD68 is likely associated with lipofuscin deposits in microglial cells which may be increased in DLB cases because of impaired proteostasis. Overall, we conclude that neurodegenerative changes in DLB are unlikely to result directly from activated microglia but rather from dysfunctional ones.
小胶质细胞激活（神经炎症）常被认为是神经退行性疾病发展的致病因素。然而，有一个重要的问题需要注意，即炎症是否直接导致α-突触核蛋白病理或神经纤维缠结（NFT）。我们对 5 例路易体痴呆（DLB）和 9 例非痴呆（ND）对照的颞叶和额上回组织样本进行了免疫组织化学研究，中位年龄分别为 87 岁和 74 岁，使用了三种已知标记小胶质细胞和巨噬细胞的抗体：iba1、抗 CD68 和抗铁蛋白。所有 DLB 病例均显示α-突触核蛋白病理（路易体和神经原纤维）和 NFT，范围从 Braak Ⅱ期到Ⅳ期。相比之下，所有对照均无α-突触核蛋白病理，但确实显示 NFT，范围从 Braak Ⅰ期到Ⅲ期。使用 iba1 标记，我们目前的结果显示，除了两个对照显示小灶性微胶质激活和巨噬细胞形成外，所有病例均未见明显的激活小胶质细胞。Iba1 和铁蛋白抗体均显示在整个研究区域内存在有分支和变形的小胶质细胞的混合物，并且在 DLB 和对照之间，变形小胶质细胞的患病率没有可测量的差异。α-突触核蛋白和 iba1 阳性小胶质细胞的双重标记显示，皮质路易体被有分支和变形的小胶质细胞所包围。我们发现 DLB 病例中 CD68 的表达相对于对照增加。由于小胶质细胞的营养不良与 NFT 有关，并且在 DLB 病例中似乎没有比对照更严重，我们的发现支持这样的观点，即 DLB 中额外的路易体病理不是小胶质细胞营养不良加剧的结果。CD68 可能与小胶质细胞中的脂褐素沉积有关，由于蛋白质稳态受损，DLB 病例中的脂褐素沉积可能会增加。总的来说，我们得出结论，DLB 中的神经退行性变化不太可能直接由激活的小胶质细胞引起，而是由功能失调的小胶质细胞引起的。
