Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
IRCCS, Institute of Neurological Sciences, Bologna, Italy.
Neuropathol Appl Neurobiol. 2018 Oct;44(6):574-589. doi: 10.1111/nan.12461. Epub 2018 Feb 26.
The aim of this study was to describe the regional profiles of microglial activation in sporadic Creutzfeldt-Jakob disease (sCJD) subtypes and analyse the influence of prion strain, disease duration and codon 129 genotype.
We studied the amount/severity and distribution of activated microglia, protease-resistant prion protein (PrP ) spongiform change, and astrogliosis in eight regions of 57 brains, representative of the entire spectrum of sCJD subtypes.
In each individual subtype, the regional extent and distribution of microgliosis significantly correlated with PrP deposition and spongiform change, leading to subtype-specific 'lesion profiles'. However, large differences in the ratio between PrP load or the score of spongiform change and microglial activation were seen among disease subtypes. Most significantly, atypical sCJD subtypes such as VV1 and MM2T showed a degree of microglial activation comparable to other disease variants despite the relatively low PrP deposition and the less severe spongiform change. Moreover, the mean microglial total load was significantly higher in subtype MM1 than in MM2C, whereas the opposite was true for the PrP and spongiform change total loads. Finally, some sCJD subtypes showed distinctive regional cerebellar profiles of microgliosis characterized by a high granular/molecular layer ratio (MV2K) and/or a predominant involvement of white matter (MVK and MM2T).
Microglial activation is an early event in sCJD pathogenesis and is strongly influenced by prion strain, PRNP codon 129 genotype and disease duration. Microglial lesion profiling, by highlighting strain-specific properties of prions, contributes to prion strain characterization and classification of human prion diseases, and represents a valid support to molecular and histopathologic typing.
本研究旨在描述散发性克雅氏病（sCJD）各亚型中小胶质细胞激活的区域性特征，并分析朊病毒株、疾病持续时间和密码子 129 基因型的影响。
我们研究了 57 例大脑样本中 8 个区域中激活小胶质细胞的数量/严重程度和分布、蛋白酶抗性朊蛋白（PrP）海绵状变化以及星形胶质细胞增生，这些样本代表了 sCJD 各亚型的全部范围。
在每个个体亚型中，小胶质细胞增生的区域范围和分布与 PrP 沉积和海绵状变化显著相关，导致了亚型特异性的“病变特征”。然而，在疾病亚型之间，PrP 负荷或海绵状变化评分与小胶质细胞激活之间的比值存在很大差异。最显著的是，非典型 sCJD 亚型，如 VV1 和 MM2T，尽管 PrP 沉积相对较低且海绵状变化较轻，但表现出与其他疾病变体相当的小胶质细胞激活程度。此外，亚型 MM1 的小胶质细胞总负荷明显高于 MM2C，而 PrP 和海绵状变化总负荷则相反。最后，一些 sCJD 亚型表现出独特的小脑区域性小胶质细胞增生特征，表现为颗粒/分子层比例高（MV2K）和/或白质优先受累（MVK 和 MM2T）。
小胶质细胞激活是 sCJD 发病机制中的早期事件，受朊病毒株、PRNP 密码子 129 基因型和疾病持续时间的强烈影响。小胶质细胞病变分析通过突出朊病毒的株特异性特性，有助于朊病毒株的特征描述和人类朊病毒病的分类，并为分子和组织病理学分型提供有效的支持。
