Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
University of Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, LabEx DISTALZ, Lille, France.
Glia. 2019 Dec;67(12):2329-2342. doi: 10.1002/glia.23688. Epub 2019 Jul 22.
Adenosine A receptors (A R) are modulators of various physiological processes essential for brain homeostasis and fine synaptic tuning. In certain neurodegenerative conditions, notably Alzheimer's disease (AD), A Rs are pathologically upregulated in neurons but also in astrocytes. In that context, the use of A Rs inhibitors, normalizing impaired receptor function, is seen as a potential therapeutic strategy. However, the impact of A R alterations, particularly in astrocytes, is not fully understood. Here, we investigated the effect of A R overexpression on transcriptional deregulation in primary astrocytic cultures. By performing whole transcriptome analysis, we found that A R overexpression promotes robust transcriptional changes, mostly affecting immune response, angiogenesis, and cell activation-related genes. Importantly, we observed that treatment with SCH58261, a selective A R antagonist, restored the expression levels of several inflammatory and astrocytic activation-related genes, such as Interleukin-1beta and vimentin. This supports the notion that A R blockade could restore some astrocytic dysfunctions associated with abnormal A R expression, further arguing for a potential beneficial impact of receptor antagonists in A R-induced transcriptional deregulation, inflammation, and astrogliosis. Overall, our findings provide novel insights into the putative impact of A R overexpression on transcriptional deregulation in astrocytes, thereby opening novel avenues for the use of A R antagonists as potential therapeutic strategy in neurodegenerative diseases.
腺苷 A 受体（A R）是调节各种生理过程的调节剂，这些过程对于大脑内环境稳定和精细的突触调节至关重要。在某些神经退行性疾病中，特别是阿尔茨海默病（AD）中，神经元和星形胶质细胞中 A R 的病理性上调。在这种情况下，使用 A R 抑制剂来调节受损的受体功能被视为一种潜在的治疗策略。然而，A R 改变的影响，特别是在星形胶质细胞中，尚未完全理解。在这里，我们研究了 A R 过表达对原代星形胶质细胞培养物中转录失调的影响。通过进行全转录组分析，我们发现 A R 过表达会引起强大的转录变化，主要影响免疫反应、血管生成和细胞激活相关基因。重要的是，我们观察到用 SCH58261（一种选择性 A R 拮抗剂）处理可恢复几种炎症和星形胶质细胞激活相关基因的表达水平，如白细胞介素-1β和波形蛋白。这支持了 A R 阻断可能会恢复与异常 A R 表达相关的一些星形胶质细胞功能障碍的观点，进一步证明了受体拮抗剂在 A R 诱导的转录失调、炎症和星形胶质细胞增生中的潜在有益影响。总的来说，我们的研究结果为 A R 过表达对星形胶质细胞中转录失调的潜在影响提供了新的见解，从而为使用 A R 拮抗剂作为神经退行性疾病的潜在治疗策略开辟了新的途径。
