Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Institute of Clinical Neuroanatomy, Ulm University, Helmholtzstraße 8/1, 89081 Ulm, Germany.
Cells. 2021 Oct 6;10(10):2669. doi: 10.3390/cells10102669.
Alzheimer's disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number of amyloid plaques in the cerebral cortex and hippocampus. Interestingly, isolated primary astrocytes and microglia cells exhibit specific marker gene profiles which, in the case of microglia, point to an enhanced plaque clearance capacity. In contrast, direct IKK2/NF-κB activation in microglia results in a pro-inflammatory polarization program. Our findings suggest that IKK2/NF-κB signaling in astrocytes may activate paracrine mechanisms acting on microglia function but also on APP processing in neurons.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，伴随着明显的神经炎症反应，主要表现为明显的小胶质细胞和星形胶质细胞增生。然而，星形胶质细胞和小胶质细胞激活的不同方面如何影响疾病进展仍不清楚。此前，我们发现星形胶质细胞中 IKK2/NF-κB 激活引发的脊髓小胶质细胞扩张对肌萎缩侧索硬化症的进展具有阶段性的有益影响。在这里，我们使用 APP23 小鼠 AD 模型结合星形胶质细胞中 IKK2/NF-κB 信号的条件激活，研究了 NF-κB 引发的神经炎症对 AD 发病机制的影响。我们发现星形胶质细胞中 NF-κB 的激活引发了一种独特的神经炎症反应，其特征是明显的星形胶质细胞增生以及明显的小胶质细胞反应。免疫组织化学和刚果红染色显示大脑皮层和海马体中淀粉样斑块的总体大小和数量减少。有趣的是，分离的原代星形胶质细胞和小胶质细胞表现出特定的标记基因谱，在小胶质细胞中，这表明其具有增强的斑块清除能力。相比之下，小胶质细胞中 IKK2/NF-κB 的直接激活会导致促炎极化程序。我们的研究结果表明，星形胶质细胞中的 IKK2/NF-κB 信号可能激活旁分泌机制，作用于小胶质细胞功能，也作用于神经元中的 APP 处理。
