Zhu Xiaoyue, Schrader Joseph M, Irizarry Brandon A, Smith Steven O, Van Nostrand William E
George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA.
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Biomedicines. 2022 Nov 19;10(11):2982. doi: 10.3390/biomedicines10112982.
Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer's disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of , , , , and in plaque-associated microglia, and , , and in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including and in astrocytes, and microglial activation and in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment.
大脑中由Aβ40或Aβ42肽主要组成的纤维状淀粉样β蛋白（Aβ）沉积物是阿尔茨海默病（AD）及相关疾病的关键病理特征。尽管其潜在机制仍不清楚，但Aβ纤维可引发多种细胞反应，包括星形胶质细胞和小胶质细胞的激活。此外，已知Aβ40和Aβ42肽的纤维结构具有多态性，这给确定不同Aβ序列和结构对脑病理学的贡献带来了挑战。在此，我们用特征明确的单一Aβ40或Aβ42纤维多态体系统地处理原代星形胶质细胞和小胶质细胞，并进行大量RNA测序以评估基因表达的细胞特异性变化。与Aβ40纤维处理的胶质细胞（星形胶质细胞和小胶质细胞中分别为191和251个基因）相比，Aβ42纤维处理的胶质细胞（星形胶质细胞和小胶质细胞中分别为251和2133个基因）上调的基因数量更多。在具有实质纤维状Aβ42斑块的AD大鼠模型中进行的免疫标记研究证实，斑块相关小胶质细胞中 、 、 、 和 的表达，以及斑块相关星形胶质细胞中 、 和 的表达，验证了RNA序列数据中的标记物。为了更好地理解这些Aβ纤维诱导的基因变化，我们使用Ingenuity通路分析程序分析基因表达模式。这些分析进一步强调，Aβ42纤维处理上调了胶质细胞中的细胞激活途径和免疫反应途径，包括星形胶质细胞中的 和 ，以及小胶质细胞中的小胶质细胞激活和 。进一步分析表明，在Aβ40纤维处理的小胶质细胞中，许多疾病相关小胶质细胞（DAM）基因出人意料地受到抑制。总之，目前的研究结果表明，与Aβ40纤维处理相比，Aβ42纤维通常对胶质细胞表现出相似但更强的刺激活性。
Zotero 插件
